Erythropoietin Resistance In Patients Research Articles

The Impact of Genetic Polymorphisms in (STIM1 and ORAI1) on Erythropoietin Resistance in Patients with Chronic Renal Failure on Hemodialysis in Iraq

Objective: This study aims to investigate the correlation between genetic polymorphisms in store-operated calcium channels (SOCs) signaling and resistance to erythropoietin treatment in patients with chronic renal failure (CRF). Anemia is a significant complication of CRF, and understanding the genetic factors contributing to resistance could provide insights into potential mechanisms influencing treatment outcomes. Specifically, the focus is on exploring the relationship between SOCs, a pathway activated by erythropoietin, and resistance to address the challenges associated with anemia in CRF patients.
 Methods: In this study, a single nucleotide polymorphism in each STIM1 and ORAI1 gene was selected. Genotyping was done by using allele specific polymerase chain reaction technique and the data was analyzed through the Statistical Package for the Social Sciences. 112 patients with CRF on hemodialysis were enrolled 58.9% of them were men and the mean age was 50.94±13.42.
 Results: We found that CC genotype of ORAI1 gene has a higher hemoglobin level, AA genotype of STIM1 has a higher EPO level, the interaction of the two genes showed that CCGG group has a higher Hb level and is considered good responder but represents only 4.5% of the patients
 Conclusion: After all the genetic polymorphisms of SOCs genes ORAI1 and STIM1 have no significant impact on erythropoietin resistance in patients with CRF on hemodialysis in Iraq.

Risk Factors Involved in Erythropoietin Resistance in Patients with CKD in a Hemodialysis Unit

Risk Factors Involved in Erythropoietin Resistance in Patients with CKD in a Hemodialysis Unit

Soluble Anti- Erythropoietin Level as a Predictor of Erythropoietin Resistance in Patients under Regular Hemodialysis

Soluble Anti- Erythropoietin Level as a Predictor of Erythropoietin Resistance in Patients under Regular Hemodialysis

Erythropoietin resistance in patients with regular hemodialysis in Sohag university hospital

Background: A definite anemia [hemoglobin (HB) 10-12 g/dl] or the need for significantly higher Erythropoietin (EPO) dosages of epoetin alfa are symptoms of EPO resistance, respectively. The recommended restorative goal is to maintain HB levels between 11 and 12 g/dl. Fe deficiency, concurrent inflammation, inadequate dialysis, hyperparathyroidism, hemolysis, vitamin B12, and folate deficiency are the main causes of EPO resistance. The objective of this study was to evaluate patients who receive frequent hemodialysis for EPO resistance. Methods: This study was performed at Sohag University Hospital on 50 hemodialysis patients compared to 40 healthy adult subjects from June 2021 to January 2022. Serum EPO was analyzed by enzyme-linked immunosorbent assay and Angiotensin Converting Enzyme (ACE) rs1799752 polymorphism was assessed using the Genomic TaqMan genotyping test. Results: This study found insignificant relation between EPO Resistance Index (ERI) and diverse ACE genotype groups and para thyroid hormone. A further significant direct proportional relationship was found between ERI and Ferritin. EPO and parathyroid hormone did not show any significant relationship. Conclusion: Considering the non-critical connection between ERI and our components, it is vital to enhance the treatment of anemic patients with chronic kidney diseases to recognize the potential causes of resistance and ponder other variables for resistance before proposing an expanded EPO-stimulating agent administration.

MO798: Impact of Body Composition on Erythropoietin Resistance Index in Patients Receiving Chronic Hemodialysis

Abstract BACKGROUND AND AIMS Erythropoietin resistance index (ERI) seems to be a predictor for adverse outcomes in patients receiving chronic hemodialysis. Despite the role of erythropoietin in non-hematopoietic tissues such as skeletal muscle or fat, clinical studies investigating the association between body composition and ERI are still lacking. The aim of this study was to examine the longitudinal impact of body composition on ERI in patients on chronic hemodialysis. METHOD This study included outpatients on chronic hemodialysis who received body composition analysis, which was performed every 6 months. The ERI was calculated by dividing the weekly body weight-adjusted erythropoietin dose by the hemoglobin concentration, and the values were averaged every 3 months period. The relationship between body composition and baseline ERI was evaluated in the multiple linear regression analysis, and the trend of ERI over time according to the changes in body composition was analyzed using a linear mixed effect model. RESULTS There were 65 (52.8%) men and 58 (47.2%) women, and they were followed up for 24 (5, 75) months. Subjects with higher mean ERI during the study period had increased risks for all-cause death, cardiovascular events and infection requiring hospitalization, compared with those with lower mean ERI (P = .009, .076 and .051). Linear regression analyses found that the ERI was negatively correlated to body mass index, % body fat, arm circumference, arm muscle circumference, and visceral fat area (P = .067, .065, .002, .021 and .040). However, the ratio of extracellular water to total body water and skeletal muscle mass index was not related to ERI. The longitudinal trend of ERI was compared according to the slope of body composition parameters over time. The increase in ERI was associated with the increase in the ratio of extracellular water to total body water (P = .007). On the other hand, the trajectory of ERI was inversely related to the longitudinal changes in arm circumference, arm muscle circumference and visceral fat area (P = .002, P < .001 and P = .026). CONCLUSION The ERI seems to be associated with body composition; therefore, body composition analysis can be useful to predict erythropoietin resistance in patients receiving chronic hemodialysis. Further studies are needed to investigate whether lifestyle modifications, including nutrition and exercise, can result in positive effects on body composition and responsiveness to erythropoietin.

Change in Anemia by Carnitine Supplementation in Patients Undergoing Peritoneal Dialysis: A Retrospective Observational Study.

Background: Carnitine supplementation improves various dialysis-related symptoms including erythropoietin-resistant anemia in patients who are undergoing hemodialysis. However, the utility of carnitine supplementation in patients who are undergoing peritoneal dialysis (PD) is not fully understood.Methods: Thirteen patients undergoing PD [mean age: 54.2 ± 14.8 years, males: 9/13 (69%)] administered oral carnitine supplementation (mean dose: 9.1 ± 3.3 mg/kg/day) for 4–6 months were retrospectively investigated. Changes in serum carnitine levels and other clinical variables including the erythropoietin resistance index (ERI) were analyzed after carnitine supplementation.Results: Carnitine supplementation increased serum total carnitine (48.5 ± 10.2 vs. 130.1 ± 37.2 μmol/L, P < 0.01), free carnitine (31.1 ± 8.3 vs. 83.1 ± 24.6 μmol/L, P < 0.01), and acyl carnitine (17.4 ± 2.8 vs. 46.9 ± 13.8, P < 0.01) levels. The acyl carnitine/free carnitine ratio was not affected (0.6 ± 0.1 vs. 0.6 ± 0.1, P = 0.75). Although the mean ERI was not affected by carnitine supplementation [13.7 ± 4.7 vs. 11.6 ± 3.4 IU/kg/(g/dL)/week, P = 0.28], the ERI change rate was significantly decreased (1.00 ± 0.00 vs. 0.87 ± 0.11, P < 0.01).Conclusion: Carnitine supplementation may improve erythropoietin resistance in patients who are undergoing PD.

Factors Responsible For The Development Of Erythropoietin Resistance In Chronic Kidney Disease Patients

Chronic kidney disease (CKD) is a global socially significant health problem that now affects more than 10% of the world's population. Anemia is a common complication of CKD and is associated with reduced quality of life, increased morbidity and mortality, and higher treatment costs. Erythropoietin resistance is a common condition in the treatment of anemia in patients with CKD and is one of the most potent predictors of risk for cardiovascular events and mortality. The aim of the present study was to analyze some factors leading to the development of erythropoietin resistance in patients with chronic kidney disease. In 80 patients of the Clinic of Nephrology of St. Marina University Hospital, Varna, demographic indicators, levels of serum iron, folic acid, vitamin B12, iPTH, iFGF23, soluble erythropoietin receptor (sEPOR) and antiEPOab were studied.

Erythropoietin Resistance in Patients with Chronic Kidney Disease: Current Perspectives.

Anemia is a frequent complication of chronic kidney disease, and its primary cause is erythropoietin deficiency. After diagnosis, treatment begins with administration of an erythropoiesis-stimulating agent (ESA). However, some patients present with resistance to ESA, which needs to be reversed, as it can increase the risk of death in patients with kidney disease. Therefore, we provide a discussion of the current literature regarding the factors that can modify the response to this class of drugs and the strategies that can be considered to optimize the benefits of treating anemia.

Low 1,25-dihydroxyvitamin D level is associated with erythropoietin deficiency and endogenous erythropoietin resistance in patients with chronic kidney disease.

Erythropoietin (EPO) deficiency and resistance to endogenous EPO is an important pathophysiological feature in anemia of chronic kidney disease (CKD). Low 1,25 dihydroxyvitamin D [1,25(OH)2D] level is known to contribute to anemia of CKD. We aimed to investigate the associations between serum 1,25(OH)2D and anemia, EPO deficiency, and endogenous EPO resistance in patients with CKD. This study included 409 patients with CKD [glomerular filtration rate (GFR) < 60ml/min/1.73m2] who were not on dialysis therapy. Patients on exogenous EPO therapy and patients with iron deficiencies were excluded. Endogenous EPO resistance was assessed by calculating the ratio of endogenous EPO to hemoglobin (Hb) (endogenous EPO/Hb ratio). The associations of Hb level, endogenous EPO level, and the endogenous EPO/Hb ratio with clinical and laboratory variables were investigated by univariate and multivariate analyses. In univariate analysis, serum 1,25(OH)2D level was correlated with the Hb level, endogenous EPO level, and the endogenous EPO/Hb ratio. Multiple regression analysis revealed that the serum 1,25(OH)2D level remained significantly associated with the Hb level (β = 0.532, P < 0.001), endogenous EPO level (β = 0.149, P = 0.010), and the endogenous EPO/Hb ratio (β = - 0.187, P = 0.002), even after adjusting for other confounding factors, including the levels of parathyroid hormone and the inflammatory marker C-reactive protein. The serum 1,25(OH)2D level exhibited significant associations with anemia, EPO deficiency, and endogenous EPO resistance in CKD patients. These associations were independent of secondary hyperparathyroidism and inflammation status.

Hypersplenism, EPO resistance and chronic Salmonella infection

Abstract Chronic diseases, such as AIDS and malaria, are associated with increased susceptibility to non-typhoidal Salmonella (NTS) infection. Among the key clinical manifestations shared by these immunocompromised individuals are anemia and splenomegaly (i.e. hypersplenism), conditions also associated with NTS susceptibility. To better understand the immunological basis of hypersplenism, we developed a model of chronic NTS infection in resistant 129X1/SvJ mice transiently depleted of CD4+ T cells. NTS infection induced chronic peripheral anemia that became more severe in the absence of CD4+ T cells. While serum erythropoietin (EPO) peaked on day 21 post infection in mock-depleted mice, EPO levels continued to rise in CD4-depleted animals. The failure to resolve anemia despite high levels of EPO parallels the development of EPO resistance in patients receiving recombinant human EPO therapy. Increased accumulation of mature erythrocytes and immature erythroid precursor cells within the enlarged spleens of CD4-depleted mice suggests that chronic inflammation leads to splenic sequestration of damaged erythrocytes, thus contributing to persistent anemia. We demonstrate that sequestration of erythroid cells drives the expansion of splenic macrophages, a known reservoir for NTS survival. Our findings provide a potential mechanism to link anemia of chronic disease, hypersplenism and increased susceptibility to NTS infections.

Iron chelation therapy and its influence on the alleviation of EPO resistance in MDS patients

This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance in some patients was decreased. It is concluded that iron chelation therapy can improve the efficacy of EPO to alleviate EPO resistance in patients wtih anemic MDS, decrease the pathological level of EPO, enhance Hb levels and reduce the dependency on blood transfusion.

Protein restriction: a revisited old strategy with new opportunities?

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Comparative Study of Intravenous Iron Versus Intravenous Ascorbic Acid for Treatment of Functional Iron Deficiency in Patients Under Hemodialysis. A Randomized Clinical Trial

BackgroundFunctional iron deficiency (FID) may cause erythropoietin resistance in patients under hemodialysis (HD). Since the role of chronic inflammation or oxidative stress in its pathogenesis is unclear, controversy remains to whether intravenous iron or intravenous ascorbic acid (an antioxidant) can improve this anemia due to decreased iron availability.ObjectivesThe current study compared the effect of intravenous iron versus intravenous ascorbic acid in the management of FID in HD patients.Patients and MethodsForty HD patients with hemoglobin (Hb) ≤ 11 g/dL, serum ferritin ≥ 500 ng/mL and transferrin saturation (TSAT) ≤ 25% were randomly divided into two groups. 20 patients received 100 mg of intravenous (IV) iron (group I), and 20 patients received 300 mg of IV ascorbic acid (group II) postdialysis, twice a week for 5 consecutive weeks. Hb and iron metabolism indices were measured before the onset of the study and after 12 weeks following therapy.ResultsTwenty one percent of all HD patients, exhibited high serum ferritin, low TSAT and sufficient data for analysis. Both Group I (n = 20) and Group II (n = 20) patients showed a significant increase in Hb, serum iron, and TSAT (P < 0.001). There were no significant differences between both groups in increasing Hb (P = 0.076), serum iron (P = 0.589), serum ferritin (0.725), and TSAT (P = 0.887).ConclusionsThis study showed that both IV iron and IV ascorbic acid can improve FID in HD patients. A larger randomized trial is warranted to determine the optimal management of FID in HD patients.

Association between the malnutrition-inflammation score and post-transplant anaemia

Post-transplant anaemia (PTA) is common and is associated with adverse consequences. The protein-energy wasting (PEW) syndrome is associated with erythropoietin resistance in patients on maintenance dialysis. We assessed the association between PEW and PTA in a large prevalent cohort of stable kidney-transplanted patients. Data from 942 prevalent kidney-transplanted patients were analysed. Socio-demographic parameters, laboratory results, transplantation-related data and medication were obtained from the charts. Biomarkers reflecting nutritional status and inflammation [serum leptin, albumin, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein] were measured. Anthropometric measures and the malnutrition-inflammation score (MIS) were also tabulated. Anaemia was defined according to the guidelines of the American Society of Transplantation. Mean age was 51 ± 13 years, 57% were males and 22% had diabetes. The prevalence of PTA was 33%. The haemoglobin (Hb) level significantly and negatively correlated with the MIS (rho = - 0.316), marginally with serum TNF-α (rho = - 0.079) and serum IL-6 (rho = - 0.075) and positively with serum transferrin (r = 0.298), serum albumin (r = 0.274), abdominal circumference (r = 0.254) and serum leptin (rho = - 0.152), P < 0.05 for all. In a multivariable linear regression model, MIS was independently associated with Hb (beta = - 0.118, P = 0.004) in patients with estimated glomerular filtration rate (eGFR) lower than or equal to 60 mL/min/1.73 m(2), but not in patients with higher eGFR. The MIS is independently associated with PTA in the kidney-transplanted population with eGFR lower than or equal to 60 mL/min/1.73 m(2).

Serum 25(OH)-Cholecalciferol Concentration Is Associated with Hemoglobin Level and Erythropoietin Resistance in Patients on Maintenance Hemodialysis

Background: Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in patients with chronic kidney disease (CKD) and it is associated with clinical outcomes. The presence of ESA resistance cannot always be explained by the known risk factors of the condition, suggesting that additional factors may be involved. We wanted to test the hypothesis that vitamin D insufficiency is associated with lower hemoglobin (Hb) and ESA resistance in patients on maintenance hemodialysis (HD). Methods: Data from patients receiving maintenance HD in a single dialysis center were extracted from the medical records in a retrospective chart review. Basic patient characteristics and laboratory data including Hb, serum albumin, intact parathyroid hormone and serum 25(OH)-cholecalciferol (25(OH)D₃) levels were collected. ESA dose and Kt/V were extracted from the dialysis charts. Correlation analysis and multivariate linear regression analysis were used to reveal potential independent associations between clinical and laboratory parameters and ESA resistance. Results: Data from 142 patients were analyzed. Serum 25(OH)D₃ concentration was significantly correlated with Hb (ρ = 0.186, p < 0.05) and also with ESA dose/Hb index (ρ = 0.230, p < 0.01). In multivariable regression analyses, serum 25(OH)D₃ concentration remained significantly associated with both Hb and ESA dose/Hb index after controlling for potentially important confounders. Conclusion: Serum 25(OH)D₃ concentration is independently associated with erythropoietin responsiveness in CKD patients on maintenance HD. If this association will be confirmed, treatment trials looking at the effect of vitamin D supplementation on anemia treatment in CKD patients may be warranted.

Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Parvovirus B19 Detection by PCR in Patients with Chronic Renal Failure and Resistance to Erythropoietin: An Interim Report.

Introduction: The human parvovirus B19 (pvB19) is well known as a cause of chronic anemia and red cell aplasia, this due to the high tropism for the erythroid progenitor cells where it replicates. Some reports have suggested that the infection of this virus is related to an erythropoietin resistance in patients with chronic anemia and kidney failure. The most frequent causes of erythropoietin resistance are iron deficiency, chronic inflammation process, vitamin deficiency, hyperparathyroidism and malignancies among others. The aim of this study was to detect the viral DNA of PvB19 and its correlation with hemoglobin levels and human erythropoietin dosage in patients with kidney failure under hemodialysis treatment.Patients and Methods: All patients had chronic renal failure and were undergoing hemodialysis. The detection of the viral DNA was performed by qualitative polymerase chain reaction (PCR). The PCR reaction was carried out using one specifically designed primer set for PvB19 that encoded for a structural capsid protein (VP1). Erythropoietin resistance (ER) was diagnosed using the European Best practice Guidelines as stated by Hay N (Nephrology, 2002).Results: A total of 58 samples of peripheral blood were obtained from patients with chronic kidney failure. Mean age was 59.41 (23 to 85 years) and mean Hemoglobin levels were 10.1 g/dL (7–14). Iron was normal in all patients and no patient had active infections. Fifty two patients (89.65%) were receiving recombinant erythropoietin. Among all the samples, 3 cases met ER criteria but only in 1 of them did we find the viral DNA (1.72%). Three cases (5.17%) positive to the viral DNA were found in the non erythropoietin resistance group.Conclusion: Although ours is a small group and we are still gathering samples, up until now, no relation appears to exist between the presence of PvB19 genetic material and ER.

Single dose of acetylsalicylic acid in patients with Type 2 diabetes mellitus and/or chronic renal failure ameliorates anaemia by decreasing the rate of neocytolysis

Anaemia in diabetes mellitus (DM) and/or chronic renal failure (CRF) may be caused by a decreased production of erythropoietin (EPO), EPO resistance, and by the lysis of the young circulating red blood cells (neocytolysis) induced by subclinical inflammation and low EPO level. Aims of this study were to detect EPO resistance in patients with DM and/or CRF and to prove, that acetylsalicylic acid (ASA) is able to improve the haemopoietic status by decreasing neocytolysis. In a cross-sectional study, three groups of selected patients (patients with DM; patients with DM+CRF; patients with CRF without DM, n=15 each) and a group of controls (non-diabetic, nonazotemic subjects, n = 10) were compared. In the intervention part of the study, the effect of a single dose of 1 gram ASA on neocytolysis was investigated in a subgroup of these patients. Despite the similar EPO level (p = 1.000), all three patient groups had lower haemoglobin and haematocrit than control persons (p < 0.05 in all cases). Patients with DM+CRF had lower haemoglobin than patients with DM or CRF alone (p < 0.05). Single dose of ASA induced a fast increase in serum EPO level, a concomitant rise of the Rtc number and rate, red blood cell count, haematocrit and haemoglobin p < 0.01 for each). These changes were accompanied by a marked decrease in serum lactate dehydrogenase activity (p < 0.01). DM and CRF may induce erythropoietin resistance. In these patients, ASA treatment increases serum EPO level. The higher EPO level and the anti-inflammatory effect of ASA may decrease neocytolysis.

Gastric Antral Vascular Ectasia (Watermelon Stomach) in Patients With ESRD

In 1989, Navab et al suggested that watermelon stomach often is observed in patients with chronic renal insufficiency. On the basis of this and some later reports, an etiopathogenetic association between the 2 disorders was postulated. However, the number of relevant publications is still very limited. We describe 2 patients with end-stage renal disease (ESRD; 1 patient, hemodialysis therapy; 1 patient, peritoneal dialysis therapy) and watermelon stomach who presented with upper gastrointestinal bleeding and severe transfusion-dependent iron-deficiency anemia. In 1 patient, apart from the characteristic endoscopic findings of watermelon stomach affecting the antrum, there were vascular ectatic lesions in the proximal stomach. Both patients were treated successfully by using endoscopic bipolar electrocoagulation (Gold probe [GP]; Microvasive Boston Scientific, Natick, MA), which led to significant endoscopic and hematologic improvement. However, upper-gastrointestinal bleeding recurred in the second patient (peritoneal dialysis) because she did not consent to undergo endoscopic treatment on a regular basis. Watermelon stomach in patients with ESRD is a serious condition that can cause either acute or chronic upper-gastrointestinal bleeding. It should be considered in patients with upper-gastrointestinal bleeding and those with iron-deficiency anemia, which frequently presents as recombinant human erythropoietin resistance in patients with ESRD. Diagnosis is based on the distinctive endoscopic appearance of the antrum, but the proximal stomach also may be involved. Application of GP ablation seems to be a safe and effective treatment for watermelon stomach.