Erythropoietin-Stimulating Agent Hyporesponsiveness in Patients Living with Chronic Kidney Disease

<b><i>Background:</i></b> Erythropoietin-stimulating agent (ESA) hyporesponsiveness is commonly observed in patients with anemia secondary to chronic kidney disease (CKD). Because of its complexity, a global consensus on how we should define ESA hyporesponsiveness remains unavailable. The reported prevalence and demographic information on ESA hyporesponsiveness within the CKD population are variable with no consensus definition. <b><i>Summary:</i></b> ESA hyporesponsiveness is defined as having no increase in hemoglobin concentration from baseline after the first month of treatment on appropriate weight-based dosing. The important factors associated with ESA hyporesponsiveness include absolute or functional iron deficiency, inflammation, and uremia. Hepcidin has been demonstrated to play an important role in this process. Mineral bone disease secondary to CKD and non-iron malnutrition among other factors are also associated with ESA hyporesponsiveness. There is continued debate toward determining a gold-standard treatment pathway to manage ESA hyporesponsiveness. The development of hypoxia-inducing factor-stabilizers brings new insights and opportunities in the management of ESA hyporesponsiveness. <b><i>Key Message:</i></b> Management of ESA hyporesponsiveness involves a comprehensive multidisciplinary team approach to address its risk factors. The progression of basic and clinical research on identifying risk factors and management of ESA hyporesponsiveness brings greater hope on finding solutions to eventually tackling one of the most difficult problems in the topic of anemia in CKD.

Effects of Oral Vitamin C on Hepcidin Levels and Erythropoietin Requirements in Functional Iron Deficiency Anemia among Hemodialysis Patients

Background Hepcidin has long been postulated as a key regulatory peptide in iron homeostasis. Its reduced clearance and elevated levels in hemodialysis (HD) patients lead to functional iron deficiency (FID) and ESA resistance. Vitamin C may be used as adjuvant therapy in FID anemia, but there are limited studies investigating the direct relation between vitamin C and hepcidin levels in HD patients. We aimed to test the reducing effect of Oral vitamin C therapy on hepcidin levels among hemodialysis patients with functional iron deficiency anemia. Patients and Methods This study is an open label randomized controlled clinical trial. It was conducted in the hemodialysis units of Ain Shams University hospitals. 48 adult prevalent HD patients were included and were divided into two groups. Group 1 (study group) included 31 patients who received the conventional treatment of erythropoietin stimulating agents (ESAs) together with oral supplementation of vitamin C 500 mg every other day for 3 months in addition to IV iron therapy. Group 2 (control group) included 17 patients who received only the conventional therapy of ESAs according to their hemoglobin (Hb) levels in addition to IV iron therapy. Laboratory parameters including serum hepcidin levels, highly sensitive CRP (hs-CRP) titer, CBC, kidney function tests and iron indices were measured at the baseline of the study and after 3 months. Results Oral vitamin C therapy resulted in a statistically significant reduction in both hepcidin and hs-CRP levels in the study group after 3 months. The study group showed a significant reduction in serum iron and ferritin levels (P &lt; 0.05). A Decrease in EPO requirements and elevation of hemoglobin level were observed in the study group but were not statistically significant as a short term effect of oral vitamin C, in comparison to the control group. A highly significant correlation was observed between serum hepcidin and hs-CRP (R=0.46, P&lt;0.01). Conclusion Oral vitamin C may be a promising therapy in decreasing serum hepcidin and hs-CRP levels in prevalent hemodialysis patients with functional iron deficiency anemia.

Compliance with the National Comprehensive Cancer Network guidelines for evaluation and treatment of anemia among patients with solid tumors.

11 Background: Anemia is associated with increased morbidity, mortality and decreased quality of life among oncology patients. The National Comprehensive Cancer Network (NCCN) recommends evaluation and treatment of anemia in patients with cancer. There is a paucity of data investigating compliance with the NCCN guidelines. Methods: A retrospective study of patients diagnosed with any malignant solid tumor at our institution from 2008-2017 was performed. Tumor-registry-confirmed cancer cases were identified using International Classification of Disease-Oncology (ICD-O) codes in the Synthetic Derivative (SD) database, a de-identified copy of the electronic medical record. Patients were included if they were between the ages of 18 and 89 and had a hemoglobin (hgb) within 6 months of diagnosis. Patients were excluded if they had more than one tumor registry entry. Anemia was defined as hgb ≤11g/dL and graded using the CTCAE v.5.0. Absolute and possible functional iron deficiency were defined by NCCN guidelines. B12 and folate deficiency were defined by institutional reference values. Chi-squared tests were conducted in R (Version 3.4.4). P <.05 was interpreted as statistically significant. Results: A total of 25,018 patients met inclusion criteria. The median age was 60 years, and the most common malignancies were respiratory tract, prostate, and urologic (11% each, respectively). Of the 25,018 patients, 1,484 (17%) were noted to be anemic at time of diagnosis and 11,019 (44%) were anemic within 6 months of diagnosis. Of these patients, a plurality (N = 4,686, 43%) had grade 2 anemia and a majority (N = 9,623, 87%) had normocytic anemia. Patients with retroperitoneal/peritoneal cancers had the highest prevalence of anemia (N = 83, 75%). A total of 4,125 (37%) underwent any evaluation of their anemia, of which 1,742 (16%) had iron studies performed and 1,528 (14%) had B12 or folate studies performed. Of those with iron studies performed, 197 (11%) patients had absolute iron deficiency and 103 (6%) had possible functional iron deficiency. Of those with B12 labs, 74 (5%) had B12 deficiency and of those with folate labs, 69 (12%) had folate deficiency. Less than half of anemic patients (N = 4,318, 39%) received treatment for anemia, including blood transfusion (N = 3,528, 32%), oral iron (N = 1,279, 12%), or IV iron (N = 97, 1%). However, treatment of anemia significantly increased as grade of anemia increased (any treatment among mild: 12%; moderate: 31%; severe: 77%; χ2 [2, N = 11,019] = 3020.6; P <.001). Patients with male reproductive tract cancers had the highest prevalence of anemia evaluation (N = 57, 79%). Conclusions: Anemia is common in patients with solid tumors, yet compliance with NCCN guidelines for evaluation and treatment of anemia remains low. There are opportunities to improve compliance with NCCN guidelines for management of anemia across the spectrum of cancer care.

Effect of oral vitamin C on serum hepcidin level, iron status and inflammation among hemodialysis patients with functional iron deficiency anaemia

Introduction: Hepcidin is a key regulatory peptide in iron homeostasis, the pathogenesis of functional iron deficiency (FID) anemia and erythropoiesis-stimulating agent (ESA) resistance is contributed to the inflammatory mediated increase in the serum hepcidin levels among prevalent hemodialysis (HD) patients. Objectives: To test the reducing therapeutic effect of oral vitamin C supplements on hepcidin levels and iron status among HD patients with FID anemia. Patients and Methods: This study is an interventional prospective cohort study; 48 prevalent HD patients were enrolled. Group one: 31 patients who received the conventional treatment of erythropoietin stimulating agents together with oral supplementation of vitamin C 500 mg every other day dose for 3 months. Group two: 17 patients who received only the conventional therapy of erythropoietin stimulating agents. Patients with hemoglobin level <11 g/dL, ferritin level >200 ng/mL and transferrin saturation (TSAT) >20 % were included. Laboratory parameters: serum hepcidin, high-sensitivity C-reactive protein (hs-CRP) titre, CBC, and iron indices were measured at baseline and after 3 months. Results: On comparing the two groups, oral vitamin C in group 1 resulted in a statistically significant reduction in hepcidin levels [mean 2506.456 ± 1320.53 pg/mL to 1748.396 ± 1432.28 pg/mL (P = 0.03)], and a significant reduction in hs-CRP level [mean 8603.236 ± 2547.77 ng/mL to 5611.296 ± 2829.27 ng/mL] (P = 0.001) after three months of treatment in comparison to control group. A decrease of EPO requirement and elevation of hemoglobin level were observed in a study group with oral vitamin C. Conclusion: Oral vitamin C may be a promising therapy in decreasing serum hepcidin and inflammatory markers among prevalent HD patients with FID anemia.

Оxidative stress and endogenous intoxication in cancer patients

In the blood serum of 93 patients with various localities of the malignant process, the content of nitric oxide (NO), indicators of lipid peroxidation (POL): superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione in red blood cells were determined. 9 patients with ovarian cancer were examined during chemotherapy (6 courses), 40 patients with colon cancer, previously operated, were with malignant liver damage. In 39 patients with anemia, NO indicators were compared with the level of interleukin 6 (IL-6) and hepcidin-25 (GP-25). As a control, 60 practically healthy individuals were examined. It was shown that the NO content was significantly reduced in 69.7% of patients, regardless of the location of the primary tumor. There was a gradual increase in the NO content before each course of chemotherapy. A high concentration of NO (more than 22 µM) was detected in 22 patients with functional iron deficiency (FJ) against the background of anemia of chronic diseases (AHZ), which was accompanied by hyperexpression of IL-6 (27.0±10.5 pg/ml) and GP-25 (25.2±7.1 ng/ml). In contrast, the lowest NO values (less than 22 µM) were observed in 17 patients with IDA. There is no doubt that there is a certain relationship between the development of oxidative stress with the accumulation of highly toxic lipoperoxidation products that affect the overall homeostasis of the body, and the development of anemic syndrome.

Comparative Characteristics Of Ferrokinetic Parameters And Their Relationship With Inflammation In Patients With CHF In Advanced And Senile Age

To perform a comparative analysis of anemia of chronic disease (ACD) and iron-deficiency anemia (IDA) in late middle-aged and elderly patients with chronic heart failure (CHF) by ferrokinetic parameters, inflammation indexes, and their associations. Materials and methods. 65 patients with ischemic heart disease were evaluated, including 35 patients with CHF and ACD, 10 patients with CHF and IDA, and 20 patients without CHF, ACD, and IDA (control group, CG). Results. Patients with CHF and IDA had true iron deficiency whereas 54% of patients with CHF and ACD had functional iron deficiency, and 46% of patients had no iron deficiency. Levels of acute phase proteins, ferritin and hepcidin, C-reactive protein (CRP), and interleukin-6 (IL-6) were highly significantly different in patients with CHF and ACD and patients with CHF and IDA; positive and significant correlations were found for levels of IL-6 and ferritin, IL-6 and CRP, and CRP and hepcidin. In patients with CHF and IDA, levels of acute phase proteins, ferritin and hepcidin, CRP, and IL-6 were low and correlations of IL-6 with ferritin, IL-6 with CRP, and CRP with hepcidin were non-significant. Concentrations of erythropoietin were significantly higher in patients with CHF and ACD and patients with CHF and IDA compared to the control group; however, significant differences between them were absent.

Compensating functional iron deficiency in patients with allergies with targeted micronutrition

SummaryIron deficiency is associated with atopy. Iron deficiency during pregnancy increases the risk of atopic diseases in children, while both allergic children and adults are more likely to have iron deficiency anemia. Immunologically, iron deficiency leads to activation of antigen-presenting cells, promotion of Th2 cells and enables antibody class switch in B cells. In addition, iron deficiency primes mast cells for degranulation, while an increase in their iron content inhibits their degranulation. Many allergens, especially those with lipocalin and lipocalin-like protein structures, are able to bind iron and either deprive or supply this trace element to immune cells. Thus, a local induced iron deficiency will result in immune activation and allergic sensitization. However, lipocalin proteins such as the whey protein β‑lactoglobulin (BLG) can also transport micronutrients into the defense cells (holo-BLG: BLG with micronutrients) and hinder their activation, thereby promoting tolerance and protecting against allergy. Since 2019, several clinical trials have also been conducted in allergic subjects using holo-BLG as a supplementary balanced diet, leading to a reduction in symptom burden. Supplementation with holo-BLG specifically supplied defense cells with micronutrients such as iron and therefore represents a new dietary approach to compensate for functional iron deficiency in allergy sufferers.

Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents

Anemia is a common complication in chronic kidney disease (CKD), and is associated with a reduced quality of life, and an increased morbidity and mortality. The mechanisms involved in anemia associated to CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis stimulating agents (ESA). However, these treatments have associated risks, and sometimes are insufficiently effective. Nonetheless, in the last years, there have been some remarkable advances in the treatment of CKD-related anemia, which have raised great expectations. On the one hand, a novel family of drugs has been developed: the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). These agents induce, among other effects, an increase in the production of endogenous EPO, improve iron availability and reduce hepcidin levels. Some of them have already received marketing authorization. On the other hand, recent clinical trials have elucidated important aspects of iron supplementation, which may change the treatment targets in the future. This article reviews the current knowledge of the pathophysiology CKD-related anemia, current and future therapies, the trends in patient management and the unmet goals.