All women who delivered in each of the participating UMR , Paris, France facilities during the baseline and post-intervention periods were included. The intervention, implemented over a A Dumont MD ; Research period of 2 years at the hospital level, consisted of an initial interactive workshop and quarterly educational clinically- Centre of CHU Sainte-Justine, University of Montreal, Canada oriented and evidence-based outreach visits focused on maternal death reviews and best practices implementation. This study is registered with ClinicalTrials. No hospitals were lost to center of the Commune V, follow-up.
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Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.
Anemia in CKD is typically normocytic, normochromic, and hypoproliferative. The demonstration of a circulating factor responsible for stimulating erythropoiesis, and the kidney as the main source of erythropoietin EPO in the s 3 , 4 engendered the hypothesis that EPO deficiency is a predominant cause of anemia in CKD.
Purification and cloning of EPO in the late s and s 5 — 7 enabled the development of immunologic assays for quantitating levels of circulating EPO. Although generally normal or slightly increased in anemia of CKD, EPO levels are considered inappropriately low relative to the degree of anemia, because similarly anemic patients with normal kidney function have 10— times higher EPO levels.
Anemia management was revolutionized in the late s with the introduction of recombinant human EPO. This and related erythropoiesis stimulating agents ESAs greatly benefited patients by improving their debilitating symptoms, and freeing them from dependence on blood transfusions with their associated complications secondary iron overload, infections, and sensitization impeding transplantation.
Why would ESAs have these adverse effects? These findings have renewed interest in understanding the molecular mechanisms of anemia in CKD, with the hope of developing new therapies that more closely target the underlying pathophysiology of low hemoglobin.
Numerous studies suggest that circulating uremic-induced inhibitors of erythropoiesis contribute to the anemia, although this has been disputed in some studies and no specific inhibitors have been identified.
Based on its ability to donate and accept electrons, iron is essential for many important biologic reactions, including oxygen transport, cellular respiration, and DNA synthesis. However, this same property makes excess iron toxic by generating free radicals that can damage or destroy cells. Systemic and cellular iron levels must therefore be tightly regulated. The majority of iron 20—25 mg is provided by recycling from senescent red blood cells, which are phagocytosed by reticuloendothelial macrophages to store iron until it is needed, with lesser amounts provided by dietary absorption in the duodenum 1—2 mg and release from liver stores.
Plasma iron, which circulates bound to transferrin, is relatively limited at 3 mg, and therefore must be turned over several times to meet the daily requirements for erythropoiesis. With no regulated mechanism for iron removal, typical iron losses are 1—2 mg daily, mainly from intestinal and skin cell shedding and menstruation in reproductive-age women. Systemic iron balance is therefore maintained by regulating dietary iron absorption and iron release from storage sites in the liver and reticuloendothelial macrophages.
CKD patients have increased iron losses, estimated at 1—3 g per year in hemodialysis patients, due to chronic bleeding from uremia-associated platelet dysfunction, frequent phlebotomy, and blood trapping in the dialysis apparatus. Indeed, oral iron was no better than placebo and was less effective than intravenous iron at improving anemia, improving or preventing iron deficiency, or reducing ESA dose in hemodialysis patients. Thus, CKD patients are prone to true iron deficiency, and iron supplementation is part of mainstay of anemia treatment in CKD.
Intravenous iron is preferred for hemodialysis patients because of impaired dietary iron absorption. In addition to true iron deficiency, many CKD patients have functional iron deficiency, characterized by impaired iron release from body stores that is unable to meet the demand for erythropoiesis also called reticuloendothelial cell iron blockade. These patients have low serum transferrin saturation a measure of circulating iron and normal or high serum ferritin a marker of body iron stores.
Some of these patients are treated with intravenous iron, a trend that seems to be increasing with the recent controversy surrounding ESAs. One limitation is that high serum ferritin is not specific for increased body iron stores because ferritin is also affected by infection, inflammation, liver disease, and malignancy.
Recent data suggest that hepcidin excess may account for the impaired dietary iron absorption and reticuloendothelial cell iron blockade present in many CKD patients. Discovered independently by three groups in —, 30 — 32 hepcidin is the main hormone responsible for maintaining systemic iron homeostasis. The development of assays to measure bioactive hepcidin in the last 2—3 years has ignited a profusion of studies investigating the role of hepcidin excess in the anemia of CKD.
Numerous studies now show that hepcidin is elevated in CKD patients. Complicating factors are the lack of uniformity in hepcidin measurements by different assays, 37 and the complex interplay of various factors that influence hepcidin levels in CKD patients, including iron, inflammation, and reduced renal clearance that tend to increase hepcidin, and anemia, ESAs, dialysis clearance, and hypoxia that tend to reduce hepcidin.
Recognition of a key role for hepcidin excess in causing the functional iron deficiency and anemia of CKD has ignited interest in targeting the hepcidin-ferroportin axis as a new treatment strategy for this disease. Importantly, in CKD patients with hepcidin excess, large intravenous boluses of iron would be predicted to have limited effectiveness because much of the iron is rapidly taken up by the liver and sequestered, and the remainder that is incorporated into red blood cells would be recycled ineffectively.
In addition, intravenous iron itself would further increase in hepcidin levels 35 and worsen this phenomenon. In summary, anemia of CKD is a multifactorial process due to relative EPO deficiency, uremic-induced inhibitors of erythropoiesis, shortened erythrocyte survival, and disordered iron homeostasis.
Recent work has identified hepcidin excess as a main contributor to the disordered iron homeostasis and anemia of CKD by impairing dietary iron absorption and iron mobilization from body stores Figure 1. Improving our understanding of the molecular mechanisms underlying anemia of CKD holds promise for developing new pharmacologic agents that more closely target the underlying pathogenic mechanisms of this disease for improved efficacy and reduced treatment-related adverse outcomes.
Schematic representation of the mechanisms underlying anemia of CKD. Iron and EPO are crucial for red blood cell production in the bone marrow.
Iron availability is controlled by the liver hormone hepcidin, which regulates dietary iron absorption and macrophage iron recycling from senescent red blood cells. There are several feedback loops that control hepcidin levels, including iron and EPO.
In CKD patients particularly in end stage kidney disease patients on hemodialysis , hepcidin levels have been found to be highly elevated, presumably due to reduced renal clearance and induction by inflammation, leading to iron-restricted erythropoiesis. CKD also inhibits EPO production by the kidney, and may also lead to circulating uremic-induced inhibitors of erythropoiesis, shortened red blood cell lifespan, and increased blood loss.
Black and gray arrows represent normal physiology black for iron and hormonal fluxes, gray for regulatory processes. Colored arrows represent the additional effects of CKD blue for activation, red for inhibition. RBC, red blood cell. Published online ahead of print. Publication date available at www. National Center for Biotechnology Information , U. J Am Soc Nephrol. Published online Aug Jodie L. Babitt and Herbert Y. Author information Copyright and License information Disclaimer.
Corresponding author. Correspondence: Dr. Babitt or Dr. Herbert Y. Email: ude. This article has been cited by other articles in PMC. Abstract Anemia is a common feature of CKD associated with poor outcomes.
Open in a separate window. Figure 1. Disclosures J. Acknowledgments J. Footnotes Published online ahead of print. References 1. Bright R: Cases and observations: Illustrative of renal disease accompanied by the secretion of albuminous urine.
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Left Ventricular Hypertrophy in Chronic Kidney Disease Patients: From Pathophysiology to Treatment
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Mechanisms of Anemia in CKD
Cardiovascular diseases represent the main causes of morbidity and mortality in patients with chronic kidney disease CKD. According to a well-established classification, cardiovascular involvement in CKD can be set in the context of cardiorenal syndrome type 4. Left ventricular hypertrophy LVH represents a key feature to provide an accurate picture of systolic-diastolic left heart involvement in CKD patients. According to the definition of cardiorenal syndrome type 4, kidney disease is detected before the development of heart failure, although timing of the diagnosis is not always possible.
Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia. Anemia in CKD is typically normocytic, normochromic, and hypoproliferative.
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