The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

The prognostic value of hypoxia biomarkers in older patients with chronic heart failure

Chronic kidney disease (CKD) worsens the prognosis of chronic heart failure (CHF). Hypoxia is the leading link in pathogenesis, especially in older patients with comorbidity. The aim of this study was to investigate the prognostic value of biomarkers of myocardial, renal dysfunction and hypoxia in older patients with CHF. Materials and methods 80 older hypertensive patients with CHF (48 females, mean age 70.7±8.7 years) were examined. CHF was defined according to ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, 2016. CKD was diagnosed and classified according to the KDIGO guidelines (2012). Serum levels of hypoxia-inducible factor 1-alpha (HIF-1α), endogenous erythropoietin (eEPO), N-terminal propeptide of type B natriuretic hormone (NT-proBNP), cystatin C were assessed. The follow-up period was 12 months; the primary endpoint was total mortality. Results CKD was diagnosed in 49 (61.3%) older patients with CHF. The HIF-1α level was significantly higher in the group of deceased patients than in the survivors (0.08 (IQR 0.06; 0.11) and 0.05 (IQR 0.04; 0.07) ng/ml, p=0.02), as well as the level of NT-proBNP (1126.3 (IQR 551.8; 2750.0) and 164.4 (IQR 135.5; 1100.9) pg/ml, p<0.0001), eEPO (16.92 (ICR 5.43; 64.57) and 5.36 (IQR 1.65; 8.85) mIU/ml, p<0.0001), cystatin C (1.49 (ICR 0.86; 2.13) and 0.99 (IQR 0.82; 1.32) Mg/l, p=0.0005). Cox regression analysis adjusted for sex, age and comorbidity (χ2=36.8, p<0.0001) showed that endogenous erythropoietin, independently of other factors and biomarkers, determined the prognosis of annual mortality in patients with chronic heart failure (HR 3.27 (95% CI 1.08–9.91, p=0.03); χ2=30.7, p=0.0002). When constructing classification trees, in older patients with CHF in the presence of eEPO less than 16.19 mIU/ml NT-proBNP more than 232.5 pg/ml is an unfavorable factor (in patients with NT-proBNP <232.5 pg/ml the risk decreased to 0) (for model: sensitivity – 57.1%; specificity – 92.3% (AUC=0.87); p=0.0015). Conclusions The level of eEPO in older patients with CHF has an independent and closer relationship with the annual mortality of patients than the NT-proBNP – currently accepted biomarker of the severity and prognosis of CHF. FUNDunding Acknowledgement Type of funding sources: None.

Oxidative stress as a factor in the deterioration of oxygen transfer during exercise

Blood oxygen transport regulation by physical activity increase within training dynamics is provided with different mechanisms: from the quantitative and qualitative erythron restructure (including endogenous erythropoietin rise and main erythrocyte index shifts) to change in haemoglobin affinity to oxygen, its heterogeneous structure and blood flow growth as a result of endothelium hyperpolarisation. However, the erythrocyte itself remains a key performer in blood velocity control, due to its structure and functions. This review summarizes the data of modern scientific literature on the characteristics of erythrocytes, which make these cells one of the key links in the oxygen transport system of the blood. The focus on this property of erythrocytes during physical activity is based on the fact that the athlete’s muscles must be supplied with enough oxygen to ensure high performance. Specific training and extra-training factors affecting the content of erythrocytes have been determined. The membrane structure is treated as a significant erythrocyte part in determining its deformation and microvascular blood transport. Enzymes associated with the erythrocyte membrane and affecting cell viability and performance are described. Besides, it is stressed on monitoring erythrocyte indices via modern equipment and assessing lipid peroxidation, which leads to disorders in erythrocyte membrane structure and functions.

Physiological and Clinical Impact of Repeated Inhaled Oxygen Variation on Erythropoietin Levels in Patients After Surgery

The “Normobaric Oxygen Paradox” (NOP) is a physiologic mechanism that induces an increase of endogenous erythropoietin (EPO) production by creating a state of relative hypoxia in subjects previously exposed to hyperoxia, followed by a rapid return to normoxia. Oxygen exposure duration and inspired oxygen fraction required to observe a significant increase in EPO or hemoglobin are not clearly defined. Consequently, we here study the effect of one model of relative hypoxia on EPO, reticulocytes and hemoglobin stimulation in patients after surgery. Patients were prospectively randomized in two groups. The O2 group (n = 10) received 100% oxygen for 1 h per day for eight consecutive days, via a non-rebreathing mask. The control group (n = 12) received no oxygen variation. Serum EPO, hemoglobin and reticulocyte count were measured on admission and postoperatively on days seven and nine. Percentage EPO at day nine with respect to the baseline value was significantly elevated within the groups [O2 group: 323.7 (SD ± 139.0); control group: 365.6 (SD± 162.0)] but not between them. No significant difference was found between the groups in terms of reticulocytes count and hemoglobin. Our NOP model showed no difference on EPO increase between the two groups. However, both groups expressed separately significant EPO elevation.

Current Status of Renal Anemia Pharmacotherapy—What Can We Offer Today

Chronic kidney disease (CKD) is one of the fastest-growing major causes of death internationally. Better treatment of CKD and its complications is crucial to reverse this negative trend. Anemia is a frequent complication of CKD and is associated with unfavorable clinical outcomes. It is a devastating complication of progressive kidney disease, that negatively affects also the quality of life. The prevalence of anemia increases in parallel with CKD progression. The aim of this review is to summarize the current knowledge on therapy of renal anemia. Iron therapy, blood transfusions, and erythropoietin stimulating agents are still the mainstay of renal anemia treatment. There are several novel agents on the horizon that might provide therapeutic opportunities in CKD. The potential therapeutic options target the hepcidin–ferroportin axis, which is the master regulator of iron homeostasis, and the BMP-SMAD pathway, which regulates hepcidin expression in the liver. An inhibition of prolyl hydroxylase is a new therapeutic option becoming available for the treatment of anemia in CKD patients. This new class of drugs stimulates the synthesis of endogenous erythropoietin and increases iron availability. We also summarized the effects of prolyl hydroxylase inhibitors on iron parameters, including hepcidin, as their action on the hematological parameters. They could be of particular interest in the out-patient population with CKD and patients with ESA hyporesponsiveness. However, current knowledge is limited and still awaits clinical validation. One should be aware of the potential risks and benefits of novel, sophisticated therapies.

Endogenous erythropoietin at birth is associated with neurodevelopmental morbidity in early childhood

Background New biomarkers that predict later neurodevelopmental morbidity are needed. This study evaluated the associations between umbilical cord serum erythropoietin (us-EPO) and neurodevelopmental morbidity by the age of 2–6.5 years in a Finnish cohort. Methods This study included 878 non-anomalous children born alive in 2012 to 2016 in Helsinki University Hospitals and whose us-EPO concentration was determined at birth. Data of these children were linked to data from the Finnish Medical Birth Register and the Finnish Hospital Discharge Register. Neurodevelopmental morbidity included cerebral palsy, epilepsy, intellectual disability, autism spectrum disorder, sensorineural defects, and minor neurodevelopmental disorders. Results In the cohort including both term and preterm children, us-EPO levels correlated with gestational age (r = 0.526) and were lower in premature children. High us-EPO levels (>100 IU/l) were associated with an increased risk of severe neurodevelopmental morbidity (OR: 4.87; 95% CI: 1.05–22.58) when adjusted for the gestational age. The distribution of us-EPO levels did not differ in children with or without the later neurodevelopmental diagnosis. Conclusions Although high us-EPO concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the role of us-EPO determination in clinical use appears to be minor. Impact We determined whether endogenous umbilical cord serum erythropoietin would be a new useful biomarker to predict the risk of neurodevelopmental morbidity. This study evaluated the role of endogenous erythropoietin at birth in neurodevelopmental morbidity with a study population of good size and specific diagnoses based on data from high-quality registers. Although high umbilical cord serum erythropoietin concentration at birth was associated with an increased risk of neurodevelopmental morbidity in early childhood, the clinical value of erythropoietin determination appears to be minor.

Endogenous erythropoietin concentrations and association with retinopathy of prematurity and brain injury in preterm infants

Background Endogenous erythropoietin (EPO) concentrations vary widely in preterm infants and may be associated with perinatal risk factors and neurological outcomes. Erythropoietin is elevated in fetal hypoxia but is also a potential neuroprotectant. Methods In a prospective study of 27 infants ≤ 30 weeks gestation, serum erythropoietin concentrations were measured during the first month of life, on day 1 and weeks 1, 2, and 4, and related to perinatal risk factors and outcomes including retinopathy of prematurity and cerebral injury evaluated near term-equivalent post menstrual age using magnetic resonance imaging with quantitative scoring. Results Lower birth weight was associated with higher EPO concentrations throughout the first 2 weeks of life (r = -0.6, p < 0.01). Higher day 1 and week 1 EPO concentrations were associated with lower Apgar score at 1 minute (r = - 0.5) and 5 minutes (r = -0.7), respectively (p < 0.01). Higher day 1 EPO concentrations and 2-week area under the curve were associated with increased risk (p = 0.01) and severity (r = 0.5, p < 0.02) of retinopathy of prematurity. Higher EPO concentrations at 2 weeks were associated with increased total brain injury score (r = 0.5, p < 0.05). Conclusion Elevated endogenous erythropoietin concentrations in the first two weeks of life are associated with lower birth weight and increased risk of adverse outcomes.

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.