Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study.

PURPOSE: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. METHODS: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). RESULTS: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. CONCLUSION: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association.

Does Native Vitamin D Supplementation Have Pleiotropic Effects in Patients with End-Stage Kidney Disease? A Systematic Review of Randomized Trials.

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker C-reactive protein. Included trials were heterogeneous with regards to outcomes, and the majority studied small participant populations with a relatively short follow-up. We conclude that vitamin D supplementation corrects vitamin D deficiency and is safe and well-tolerated in humans with ESKD. However, it is not clear from clinical trials conducted to date that a causal pathway exists between 25(OH)D and pleiotropic effects that is responsive to vitamin D treatment.

Neonatal Anemia.

All neonates experience a downtrend in their hematocrit values immediately following the birth through normal falls in erythropoietin (Epo) production, transition to adult hemoglobin, and hemodilution with somatic growth. However, this drop is more pronounced in critically ill and preterm neonates and can lead to potentially pathologic anemia that impairs tissue oxygen delivery. In this review, we highlight the mechanisms underlying physiologic anemia and anemia of prematurity and briefly review the evidence for the treatment of anemia in the neonatal population, including the use of red blood cell transfusions, erythropoietic stimulating agents, and iron supplementation.

The effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

Anemia after kidney transplantation.

Anemia is a frequent complication in pediatric kidney transplant recipients (KTR) with a variable reported prevalence estimated between 20 and 80% depending on how defined. Causes of and risk factors for post-transplantation anemia (PTA) are multifactorial with iron deficiency being the primary cause of early PTA (within the first 6 months after transplantation) and impaired glomerular filtration rate (GFR) commonly responsible for late PTA (after 6 months). Medications, viral infections, chronic inflammation, and comorbidities also play a role. PTA has relevant long-term consequences and is a potential risk factor for allograft dysfunction, cardiovascular morbidity, and mortality. Thus, an anemia evaluation, approximately 3 months post-transplantation, is recommended in order to start early treatment and improve prognosis. Iron status, vitamin B12, folate, markers of hemolysis, and viral PCR should be checked, and medications, in particular combinations of medications, should be carefully evaluated. PTA treatment may be challenging and should be directed to the underlying causes. Iron supplementation and erythropoietin therapy, not extensively used in KTR, may be indicated. Every effort should be made to avoid blood transfusions in the pre-transplant period to avoid allosensitization. Anemia should be corrected to prepare candidates for kidney transplantation in order to reduce the need for perioperative blood transfusions as well.

Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure.

In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the "cytosolic iron depletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe2+ that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the "cytosolic iron repletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe2+, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the "cytosolic iron repletion hypothesis" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.

Innovations thérapeutiques dans la prise en charge de l'anémie de la maladie rénale chronique Therapeutic innovations in the management of chronic kidney disease-associated anemia.

Anemia is a common complication of chronic kidney disease (CKD). The insufficient erythropoietin (EPO) production by the kidneys and iron deficiency are the main causes. Iron supplementation and the administration of recombinant EPO are the main treatment modalities. New iron formulations that can be administered orally, intravenously or directly via the dialysate have recently been developed to improve efficacy and tolerance. Ferric citrate administered orally can effectively corrects anemia in case of iron deficiency and in addition chelate phosphate in the gut lumen. Ferric carboxymaltose allows intravenous administration of larger doses given less frequently. Ferric pyrophosphate citrate administered directly via the dialysate allows the compensation of iron losses during the hemodialysis session. HIF-prolyl-hydroxylase inhibitors are a new therapeutic class of erythropoiesis-stimulating agents. Orally administered, they act by stabilizing the HIF transcription factor involved in the initiation of erythropoietin production by hypoxia. Several clinical studies have recently evaluated these new molecules in comparison with recombinant EPO. In CKD patients not yet on dialysis or undergoing dialysis therapy non-inferiority in correcting anemia has been demonstrated compared with recombinant EPO. The decrease in circulating hepcidin they induce appears greater than that induced by injectable recombinant EPO. Presently available reports on the safety of HIF-prolyl-hydroxylase inhibitors are reassuring but need to be confirmed in longer-term studies of larger size. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.

Effects of a Novel Amino Acid Formula on Nutritional and Metabolic Status, Anemia and Myocardial Function in Thrice-Weekly Hemodialysis Patients: Results of a Six-Month Randomized Double-Blind Placebo-Controlled Pilot Study.

(1) Background: Chronic Kidney Disease (CKD) induces metabolic derangement of amino acid (AA) kinetics, eliciting severe damage to the protein anabolism. This damage is further intensified by a significant loss of AAs through hemodialysis (HD), affecting all tissues with a high metabolic turnover, such as the myocardium and body muscle mass. (2) Aim: to illustrate the effects of a novel AA mixture in boosting mitochondrial energy production. (3) Methods: A strict selection of 164 dialysis patients was carried out, allowing us to finally identify 22 compliant patients who had not used any form of supplements over the previous year. The study design envisaged a 6-month randomized, double-blind trial for the comparison of two groups of hemodialysis patients: eleven patients (67.2 ± 9.5 years) received the novel AA mix (TRG), whilst the other eleven (68.2 ± 10.5 years) were given a placebo mix that was indistinguishable from the treatment mix (PLG). (4) Results: Despite the 6-month observation period, the following were observed: maintenance of target hemoglobin values with a reduced need for erythropoiesis-stimulating agents in TRG > 36% compared to PLG (p < 0.02), improved phase angle (PhA) accompanied by an increase in muscle mass solely in the TRG group (p < 0.05), improved Left Ventricular Ejection Fraction (LVEF > 67%) in the TRG versus PLG group (p < 0.05) with early but marked signs of improved diastolic function. Increased sensitivity to insulin with greater control of glycemic levels in TRG versus PLG (p = 0.016). (5) Conclusions: the new AA mix seemed to be effective, showing a positive result on nutritional metabolism and cardiac performance, stable hemoglobin levels with the need for lower doses of erythropoietin (EPO), insulin increased cell sensitivity, better muscle metabolism with less loss of mass.

Iron supplementation in pregnant Danish women revisited: Effects on prepartum and postpartum iron deficiency, anemia, serum erythropoietin; including iron status, erythropoietin and anthropometrics in newborns. A randomized, placebo-controlled study.

OBJECTIVE: To assess effects of iron supplementation, 66 mg elemental iron daily as ferrous fumarate, on iron status markers during normal pregnancies. METHODS: Randomized, double-blind, placebo-controlled study of 119 women (62 iron-, 57 placebo -treated) and their newborns. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage (TSAT) and S-erythropoietin (S-EPO) were measured at 14-18, 24-27 weeks of gestation, prepartum, 1 and 8 weeks postpartum. RESULT: From 24-27 weeks gestation to 8 weeks postpartum, the iron group had higher Hb, S-ferritin and TSAT than the placebo group; prepartum, 11% had iron deficiency (ID) and 0% iron deficiency anemia (IDA) in the iron group, vs 60% and 18% in the placebo group; 8 weeks postpartum 1.6% in the iron group had ID and 1.6% IDA vs 14% and 7% in the placebo group. S-EPO levels in the iron group were lower than in the placebo group (p < 0.001). Mothers prepartum S-EPO values were correlated to newborns cord S-EPO values (p < 0.001). Newborns to iron treated mothers had higher cord S-ferritin levels than those to placebo treated mothers (p = 0.02). Newborn girls had higher cord S-ferritin levels than boys (p < 0.01). There was no impact of iron supplementation on the length of gestation, placental weight, or newborns birth weight. Birth weight was correlated only with mothers' body weight, length of gestation and placental weight. CONCLUSION: Iron supplementation had a "positive" impact on iron status and Hb both during pregnancy and postpartum, with a low frequency of ID/IDA and also a "positive" influence on newborns iron status.

Insights from the use of erythropoietin in experimental Chagas disease.

In addition to the long-established role in erythropoiesis, erythropoietin (Epo) has protective functions in a variety of tissues, including the heart. This is the most affected organ in chronic Chagas disease, caused by the protozoan Trypanosoma cruzi. Despite seven million people being infected with T. cruzi worldwide, there is no effective treatment preventing the disease progression to the chronic phase when the pathological involvement of the heart is often observed. Chronic chagasic cardiomyopathy has a wide variety of manifestations, like left ventricular systolic dysfunction, dilated cardiomyopathy, and heart failure. Since Epo may help maintain cardiac function by reducing myocardial necrosis, inflammation, and fibrosis, this study aimed to evaluate whether the Epo has positive effects on experimental Chagas disease. For that, we assessed the earlier (acute phase) and also the later (chronic phase) use of Epo in infected C57BL/6 mice. Blood cell count, biochemical parameters, parasitic load, and echocardiography data were evaluated. In addition, histopathological analysis was carried out. Our data showed that Epo had no trypanocide effect nor did it modify the production of anti-T. cruzi antibodies. Epo-treated groups exhibited parasitic burden much lower in the heart compared to blood. No pattern of hematological changes was observed combining infection with treatment with Epo. Chronic Epo administration reduced CK-MB serum activity from d0 to d180, irrespectively of T. cruzi infection. Likewise, echocardiography and histological results indicate that Epo treatment is more effective in the chronic phase of experimental Chagas disease. Since treatment is one of the greatest challenges of Chagas disease, alternative therapies should be investigated, including Epo combined with benznidazole.

Prevalence, treatment status, and predictors of anemia and erythropoietin hyporesponsiveness in Japanese patients with non-dialysis-dependent chronic kidney disease: a cross-sectional study.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). METHODS: We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11 g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl). RESULTS: Of the 4460 patients, 1050 (23.5%) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5% of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0% in patients with a hemoglobin level of < 11 g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors. CONCLUSIONS: Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.

Clinical Application Effects of Different Preoperative Blood Management Schemes in Older Patients with Delayed Intertrochanteric Fracture Surgery.

Introduction: Research on preoperative blood management in older patients with delayed surgery for intertrochanteric fracture is scarce, especially regarding hematopoiesis and hemostasis. We assessed the effectiveness of optimized blood management programs in older patients undergoing delayed surgery for intertrochanteric fractures. Methods: This retrospective study included 456 patients who underwent delayed surgery for intertrochanteric fractures. According to the optimized blood management plan, the patients were divided into four groups: group A was the control group; group B received 1 g of tranexamic acid (TXA) intravenously at admission; group C underwent sequential TXA treatment after admission until 1 day before surgery (1 g/day); and group D received iron supplements (200 mg/day) in addition to the treatment administered to group C, with or without recombinant human erythropoietin (rHuEPO; 40,000 IU). The primary outcomes were preoperative hidden blood loss (HBL), preoperative allogeneic blood transfusion (ABT) rate, hemoglobin (Hb) change, and actual Hb drop. Results: The Hb reduction, calculated HBL, and hospitalization duration in groups C and D were significantly lower than those in groups A and B. The preoperative ABT rates in groups C and D were significantly lower than those in groups A and B, with no significant difference between groups C and D. Discussion: The results of this study suggested that iron supplementation (with or without rHuEPO) combined with the sequential IV TXA scheme did not show a better clinical effect than the sequential IV TXA scheme in the management of patients undergoing delayed surgery for intertrochanteric fractures. Therefore, further evaluation is needed before recommending iron supplements and rHuEPO in older patients.

Assessment of iron metabolism disorders and adequate treatment of anemic syndrome in patients with breast cancer on the background of adjuvant chemotherapy.

Early and adequate correction of the anemic syndrome (AS) of cancer patients can prevent deterioration in the quality of life and be considered as a reserve for increasing the effectiveness of treatment for breast cancer (BC). The aim of the study was to assess the status of iron using modern methods of ferrokinetics in breast cancer patients on the background of adjuvant chemotherapy for early diagnosis and adequate treatment of AS. The object of the study included 21 breast cancer patients with a relatively favorable prognosis, with luminal types A and B (Her 2 / neu positive or negative), three times negative type. The examination was carried out in the postoperative period, against the background of adjuvant chemotherapy. The main metabolites of ferrokinetics were studied: hepcidin 25 (GP25); ferritin (FR); soluble transferrin receptors (rRTP); transferin (TRF); iron (Fe); erythropoietin (EPO); CRP and IL-6 indicators. AC correction was performed (ferinject, epotin-alpha, B12). 10 (47.6%) patients with breast cancer had AS. Most of them were diagnosed with IDA with microcytic, hypochromic characteristics of erythrocytes, low concentration of FR, Fe, GP25, IL-6, CRP, and high levels of TRP and rRTP. Functional iron deficiency (FDF) was established in some patients. In contrast to patients with IDA, they had a high concentration of FR, CRP and significant production of GP25, IL-6. The EPO level was not optimal for the majority of patients with AS. In isolated cases, during treatment with recombinant erythropoietins, a deficiency of vitamin B12 (cyanocobalamin) was revealed. The rational use of iron preparations, vitamins, and recombinant forms of EPO made it possible to restore Fe metabolism, stabilize the hemoglobin level, and also improve the condition of most breast cancer patients. The obtained data on IL-6, GP25, CRP indicate a certain relationship between them in the development of anemia with VDF in breast cancer patients and the need for further study of the characteristics of iron metabolism in cancer patients.

Therapeutic Effects of Mesenchymal Stem Cells Expressing Erythropoietin on Cancer-Related Anemia in Mice Model.

BACKGROUND: Cancer-related anemia (CRA) negatively influences cancer patients' survival, disease progression, treatment efficacy, and quality of life (QOL). Current treatments such as iron therapy, red cell transfusion, and erythropoietin-stimulating agents (ESAs) may cause severe adverse effects. Therefore, the development of long-lasting and curative therapies is urgently required. OBJECTIVE: In this study, a cell and gene therapy strategy was developed for in vivo delivery of EPO cDNA by way of genetic engineering of human Wharton's jelly mesenchymal stem cells (hWJMSCs) to produce and secrete human EPO protein for extended periods after transplantation into the mice model of CRA. METHODS: To evaluate CRA's treatment in cancer-free and cancerous conditions, first, a recombinant breast cancer cell line 4T1 which expressed herpes simplex virus type 1 thymidine kinase (HSV1-TK) by a lentiviral vector encoding HSV1-TK was developed and injected into mice. After three weeks, all mice developed metastatic breast cancer associated with acute anemia. Then, ganciclovir (GCV) was administered for ten days in half of the mice to clear cancer cells. Meanwhile, another lentiviral vector encoding EPO to transduce hWJMSCs was developed. Following implantation of rhWJMSCs-EPO in the second group of mice, peripheral blood samples were collected once a week for ten weeks from both groups. RESULTS: Analysis of peripheral blood samples showed that plasma EPO, hemoglobin (Hb), and hematocrit (Hct) concentrations significantly increased and remained at therapeutic for >10 weeks in both treatment groups. CONCLUSION: Data indicated that rhWJMSCs-EPO increased the circulating level of EPO, Hb, and Hct in both mouse subject groups and improved the anemia of cancer in both cancer-free and cancerous mice.

Alpha-lipoic acid improved anemia, erythropoietin resistance, maintained glycemic control, and reduced cardiovascular risk in diabetic patients on hemodialysis: a multi-center prospective randomized controlled study.

OBJECTIVE: To investigate the impact of alpha-lipoic acid (ALA) on inflammation, oxidative stress, anemia, and glycemic parameters and their association with cardiovascular risk in diabetic patients on hemodialysis. PATIENTS AND METHODS: In this multi-center, randomized, controlled study, 60 diabetic patients on hemodialysis were randomized into control group (n=30) which received Epoetin-alpha plus insulin therapy, and alpha-lipoic acid group (n=30) which received the same treatment plus alpha-lipoic acid (ALA) 600 mg once daily. Serum levels of high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), 8-hydroxy-2'-deoxyguanosine (8-OHdG), creatinine, urea, blood urea nitrogen (BUN), hemoglobin (Hb), iron parameters, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and fructosamine were measured at baseline and six months after intervention. The ankle-brachial index (ABI) was used to evaluate the clinical outcome. Erythropoietin resistance index (ERI), the weekly cost of Epoetin-alpha doses, and the total cost were calculated. RESULTS: The two groups were statistically similar at baseline. After the intervention, as compared to the control group, ALA group showed significant reductions in serum levels of hs-CRP, TNF-α, 8-OHdG (p<0.001), urea, and BUN (p=0.029) with significant elevations in Hb concentration (p<0.001), serum iron (p=0.037) and transferrin saturation (p<0.001). ALA group showed a significant decline in FBG (p=0.004), HbA1c (p<0.001), fructosamine (p=0.005), ERI (p<0.001), weekly doses, and the weekly cost of Epoetin-alpha, and the total cost (p<0.001). ALA provided a cardio-protective effect, whereas the percentage of patients with acceptable ABI (0.9-1) was significantly higher in ALA group than in the control group (p=0.024), and those with abnormally low ABI (<0.9) were lower in the ALA group. CONCLUSIONS: Due to its efficacy and safety, alpha-lipoic acid represents a pharmaco-economic supplement for diabetic patients on hemodialysis. Further trials are needed for complete evaluation of ALA effects.

Prescription rate of erythropoietin-stimulating agents is low for patients with renal impairment under non-nephrology care in a tertiary-level academic medical center in Japan.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) and iron supplements may be prescribed appropriately under nephrology care. However, there are few reports detailing the differences in prescription rates of these therapies among clinical departments. METHODS: A total of 39,585 patients with renal impairment were enrolled from a database of 914,280 patients. Patients were selected based on an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2. There were eight clinical departments from internal medicine, including nephrology. We defined a hemoglobin level less than 11.0 g/dL as anemia and set 20% of transferrin saturation and 100 ng/mL of serum ferritin as cutoff points. We compared the prescription rates of ESAs and iron supplementation based on the hemoglobin level and iron status among the patients seen across the eight clinical departments. RESULTS: The lower the eGFR, the more the number of patients seen under nephrology care. The rates of patients with no prescription were 52.3, 39.9, 45.9, and 54.3% among those with hemoglobin levels of < 8, 8 ≤ < 9, 9 ≤ < 10, and 10 ≤ < 11 g/dL, respectively. Of the patients with less than 11.0 g/dL of hemoglobin, 77.3% were prescribed ESAs under nephrology care. Meanwhile, only 18.5 and 8.2% of patients were prescribed ESAs in clinical departments of internal medicine, other than nephrology, and non-internal medicine care, respectively. CONCLUSION: Treatment for anemia has not been sufficiently performed in patients with renal impairment under non-nephrology care in a real-world clinical setting.

Pharmacological Neuroprotection of the Preterm Brain: Current Evidence and Perspectives.

Despite improvements in viability, the long-term neurodevelopmental outcomes of preterm babies remain serious concern as a significant percentage of these infants develop neurological and/or intellectual impairment, and they are also at increased risk of psychiatric illnesses later in life. The current challenge is to develop neuroprotective approaches to improve adverse outcomes in preterm survivors. The purpose of this review was to provide an overview of the current evidence on pharmacological agents targeting the neuroprotection of the preterm brain. Among them, magnesium sulfate, given antenatally to pregnant women with imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine administered to preterm infants after birth, exhibited neuroprotective effects for human preterm brain. Erythropoietin treatment of preterm infants did not result in neuroprotection at 2 years of age in two out of three published large randomized controlled trials; however, long-term follow-up of these infants is needed to come to definite conclusions. Further studies are also required to assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be implemented as neuroprotectants in clinical practice. Furthermore, other pharmacological agents showing promising signs of neuroprotective efficacy in preclinical studies (growth factors, hyaluronidase inhibitors or treatment, antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as well as stem cell- or exosomal-based therapies and nanomedicine, may prove useful in the future as potential neuroprotective approaches for human preterm brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. · Neuroprotective efficacy of several drugs in animals needs to be shown in humans..

Evaluation of recombinant human erythropoietin responsiveness by measuring erythrocyte creatine content in haemodialysis patients.

BACKGROUND: One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Eythropoiesis stimulating agent (ESA), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of ESA is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of ESA in haemodialysis patients by measuring the erythrocyte creatine content. METHODS: ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Erythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. RESULTS: ESA dose (152.4 ± 62.9 vs. 82.2 ± 45.5 units/kg/week, P = 0.0001) and erythrocyte creatine (2.07 ± 0.73 vs. 1.60 ± 0.41 µmol/gHb, p = 0.0003) were significantly higher in 27 patients with haemoglobin <10 g/dL compared to 56 patients with haemoglobin ≥10 g/dL. There was a fair correlation between ESA dose and the concentration of creatine in the erythrocytes (r = 0.55, P < 0.0001). Increase in haemoglobin (>0.1 g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine levels were significantly higher in those patients with an increase in haemoglobin compared to those without (2.04 ± 0.64 vs. 1.52 ± 0.39 µmol/gHb, p < 0.0001). When 8 variables (ESA dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, iron supplementation, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine levels emerged as the most important variable associated with increase in haemoglobin (Chi-square = 6.19, P = 0.01). CONCLUSION: Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of ESA in haemodialysis patients.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages.

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Efficacy of Different Interventions to Reduce Pre- or Perioperative Blood Transfusion Rate in Patients with Colorectal Cancer: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The high proportion of blood transfusions before and during surgery carries unnecessary risk and results in poor prognosis in colorectal cancer patients. Different pharmacological interventions (i.e., iron supplement or recombinant erythropoietin) to reduce blood transfusion rates have shown inconclusive results. METHODS: This network meta-analysis (NMA) consisted of randomized controlled trials (RCTs) comparing the efficacy of different pharmacologic interventions (i.e., iron supplementation or recombinant erythropoietin) to reduce the blood transfusion rate. NMA statistics were conducted using the frequentist model. Results: Seven RCTs (688 participants) were included in this study. The NMA demonstrated that the combination of high-dose recombinant human erythropoietin and oral iron supplements was associated with the least probability of receiving a blood transfusion [odds ratio = 0.24, 95% confidence intervals (95% CIs): 0.08 to 0.73] and best reduced the amount of blood transfused if blood transfusion was necessary (mean difference = -2.62 U, 95% CI: -3.55 to -1.70 U) when compared to the placebo/control group. None of the investigated interventions were associated with any significantly different dropout rate compared to the placebo/control group. CONCLUSIONS: The combination of high-dose recombinant human erythropoietin and oral iron supplements might be considered as a choice for reducing the rate of blood transfusion in patients with colorectal cancer. However, future large-scale RCT with long-term follow-up should be warranted to approve the long-term safety.