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Concept: Erythropoietin

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Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.

Concepts: Renal failure, Chronic kidney disease, Nephrology, Erythropoietin, Disease, Cardiovascular disease, Hyperparathyroidism, Cinacalcet

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Red cell production is primarily determined by the action of erythropoietin. Additional erythropoiesis-regulatory factors include molecules and cellular interactions occurring within the bone marrow (BM) microenvironment. Sotatercept (ACE-011) is an activin receptor ligand trap which binds several members of the TGF-β superfamily. Treatment with ACE-011 reverses bone loss and reduces the degree of osteoporosis. Surprisingly, this was accompanied by elevated hemoglobin and hematocrit levels. The mechanisms underlying the beneficial effects of ACE-011 on red cell production remain unknown. This study explores the means by which ACE-011 promotes erythropoiesis. We showed that ACE-011 does not directly affect erythroid differentiation of human CD34(+) cells in vitro. We next tested whether ACE-011 acts indirectly by affecting BM accessory cells. Conditioned media (CM) produced by BM stromal cells (SC) inhibited erythroid differentiation of CD34(+) cells while maintained their ability to proliferate. However, CM from SC treated with ACE-011 partially restored erythropoiesis coinciding with changes in the molecular and secretory profile of SC, including the expression and secretion of erythropoiesis-modulatory factors. We conclude that inhibitory factors produced by BM-SC in vitro might control erythropoiesis in vivo and that agents that reverse these microenvironmental signals may provide an approach to attenuate anemia in clinical conditions.

Concepts: Hemoglobin, Erythropoietin, Cell nucleus, Red blood cell, Bone marrow, Anemia, Hematocrit, Erythropoiesis

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OBJECTIVE: Examine the mediating effect of injectable drugs in the relationship between dialysis facility organizational status and patient mortality. STUDY SETTING: Medicare dialysis population. STUDY DESIGN: Data from the U.S. Renal Data System (USRDS) were used to identify 3,884 freestanding dialysis facilities and 37,942 Medicare patients incident to end-stage renal disease (ESRD) in 2006. The role of injectable medications was evaluated during a 2-year follow-up period by mediational analyses using mixed-effect regression models. DATA COLLECTION: USRDS data were matched with Dialysis Facility Report data from Centers for Medicare and Medicaid Services (CMS) and census data. PRINCIPAL FINDINGS: There was a strong association found between organizational status and use of injectable drugs. Large for-profit chains used significantly higher injectable medications compared with nonprofit chains and independent facilities. However, the relationship between facility organizational status and patient mortality was not found to be mediated through the higher use of injectable drugs. CONCLUSIONS: Large for-profit chain facilities administered higher IV epoetin, iron, and vitamin D dosages, but this did not result in improved survival. Given the associated costs and lack of a survival benefit, the overuse of injectable medications among the U.S. dialysis patients will likely end under the recent bundling of injectable medications without jeopardizing patient outcomes.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Erythropoietin, Dialysis, Pharmaceutical drug, Centers for Medicare and Medicaid Services

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Granulocyte colony stimulating factor (G-CSF) and erythropoietin stimulating agents (ESA) may be used to support patients during chemotherapy. We assessed whether G-CSF or ESA were associated with progression or death in patients with ovarian cancer.

Concepts: Erythropoietin, Cancer, Metastasis, Oncology, Chemotherapy, Gynecology, Gynecologic Oncology Group, Gynecologic oncology

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End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. INTRODUCTION: Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. METHODS: We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 ± 12.6 years) and 33 age-matched healthy controls. RESULTS: Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with “Kidney Disease: Improving Global Outcomes” working group PTH level categories (r = 0.36, p < 0.04). BMI correlated positively with trabecular number (r = 0.4, p < 0.02) and negatively with trabecular spacing (r = -0.37, p < 0.03) and trabecular network heterogeneity (r = -0.4, p < 0.02). Biomechanics positively correlated with BMI and negatively with BALP. CONCLUSION: Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR-pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patients.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Bone, Vitamin D, Erythropoietin, Dialysis

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Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages. In analyses of possible functional roles, an Mx1-Cre approach was applied to conditionally delete Spry1. At steady state, Spry1 deletion selectively perturbed erythroid development and led to reticulocytosis plus heightened splenic erythropoiesis. When challenged by hemolysis, Spry1-null mice exhibited worsened anemia and delayed recovery. During short-term marrow transplantation, Spry1-null donor marrow also failed to efficiently rescue the erythron. In each anemia model, however, hyperexpansion of erythroid progenitors was observed. Spry function depends on phosphorylation of a conserved N-terminal PY motif. Through an LC-MS/MS approach, Spry1 was discovered to be regulated via the erythropoietin receptor (EPOR), with marked EPO-induced Spry1-PY53 phosphorylation observed. When EPOR signaling pathways were analyzed within Spry1-deficient erythroid progenitors, hyperactivation of not only Erk1,2 but also Jak2 was observed. Studies implicate Spry1 as a novel regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity.

Concepts: Hemoglobin, Erythropoietin, Signal transduction, Red blood cell, Bone marrow, Anemia, Hematology, Erythropoiesis

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Substances that potentially enhance performance (eg, recombinant human erythropoietin [rHuEPO]) are considered doping and are therefore forbidden in sports; however, the scientific evidence behind doping is frequently weak. We aimed to determine the effects of rHuEPO treatment in well trained cyclists on maximal, submaximal, and race performance and on safety, and to present a model clinical study for doping research on other substances.

Concepts: Scientific method, Erythropoietin, Clinical trial, Human, The Canon of Medicine, Effectiveness, Avicenna, Placebo

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Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD.

Concepts: Hemoglobin, Renal failure, Chronic kidney disease, Kidney, Nephrology, Erythropoietin, Medicine, Iron

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Advances in the nutritional support of hospitalized patients in the early 1970s led to the recognition that tools were needed to evaluate the nutritional status of patients. The observation that malnutrition in patients receiving dialysis was associated with increased morbidity and mortality prompted many expert groups to develop nutritional scoring systems to be applied in these patients. Given the diverse and confusing terminologies that emerged from these publications, the International Society of Renal Nutritional and Metabolism convened an expert panel to recommend a new nomenclature and preferred methods to evaluate the nutritional status of patients with chronic kidney disease (CKD). The new and inclusive term protein-energy wasting (PEW) refers to a systematically defined condition based on certain criteria and reflects malnutrition and wasting caused not only by inadequate nutrient intake but also by depletion resulting from the inflammatory and noninflammatory conditions that prevail in this population. Serial assessment of nutritional status for detection and management of PEW is recommended using old and new scoring tools, including the Subjective Global Assessment (SGA), malnutrition inflammation score (MIS), Geriatric Nutritional Risk Index (GNRI), and PEW definition criteria. These tools, which are reliable methods and predictors of outcomes, are reviewed in this article.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Erythropoietin, Nutrition, Obesity, Essential nutrient

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Providing maintenance hemodialysis is associated with high costs and poor outcomes. In Nigeria, more than 90% of the population lives below the poverty line, and patients with end-stage renal disease (ESRD) pay out-of-pocket for maintenance hemodialysis. To highlight the challenges of providing maintenance hemodialysis for patients with ESRD in Nigeria, we reviewed records of all patients who joined the maintenance hemodialysis program of our dialysis unit over a 21-month period. Information regarding frequency of hemodialysis, types of vascular access for dialysis, mode of anemia treatment and frequency of blood transfusion received were retrieved. One hundred and twenty patients joined the maintenance hemodialysis program of our unit during the period under review. Seventy-two (60%) were males and the mean age of the study population was 47 + 14 years. The mean hemoglobin concentration at commencement of dialysis was 7.3 g/dL + 1.6 g/dL. The initial vascular access was femoral vein cannulation in all the patients. A total of 73.5% of the patients required blood transfusion at some point with 33% receiving five or more pints of blood. Only 3.3% of the patients had thrice weekly dialysis, 21.7% dialyzed twice weekly, 23.3% once weekly, 16.7% once in two weeks, 2.5% once in three weeks and 11.7% once monthly. At the time of review, 8.3% of the patients had died while 38.3% were lost to follow-up. Majority of patients with ESRD on maintenance hemodialysis in our unit were poorly prepared for dialysis, were under-dialyzed, and were frequently transfused with blood with resultant poor outcomes.

Concepts: Renal failure, Chronic kidney disease, Erythropoietin, Dialysis, Poverty, Hemodialysis, Artificial kidney, Blood transfusion