Lege Artis Medicinae



OCTOBER 21, 2007

Lege Artis Medicinae - 2007;17(10)

[Recombinant human erythropoietin has been used for more than 20 years for the treatment of renal anaemia, with epoetin-alfa and -beta representing the common traditional preparations. By the modification of the molecule’s carbohydrate moiety or structure a longer duration of erythropoietin receptor stimulation was achieved. The administration of these new molecules (darbepoetin, C.E.R.A.) once or twice a month is also sufficient to achieve serum haemoglobin target levels, making the treatment safer and more comfortable both for the patients and the personnel. These recently developed synthetic erythropoietin receptor stimulating molecules, along with recombinant human erythropoietin, are together called “Erythropoiesis Stimulating Agents”. In haemodialysed patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements. In praedialysed, transplanted or peritoneally dialysed patients, erythropoiesis stimulating agents should preferably be given subcutaneously both for economic and practical reasons. There are ongoing clinical trials with erythropoiesis stimulating molecules that can be administered by inhalation or per os. Current evidence suggests that the serum haemoglobin level should preferably not exceed 12 g/dl with the use of erythropoiesis stimulating agents. No cardiovascular protective effect of higher serum haemoglobin levels was demonstrated in two large clinical trials. Further well-designed studies are necessary to set evidence-based haemoglobin targets for erythropoiesis stimulating treatment. Arguments for a more widespread use of agents with extended duration include medical, financial and patient satisfaction reasons. The release of new erythropoiesis stimulating agents may further simplify the treatment of renal anaemia.]



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CSERNI Gábor, VÁGÓ Tibor, TÖRÖK Norbert, GAÁL Zoltán, VELKEI Tamás, SERÉNYI Péter, GÖCZŐ Katalin, TUSA Magdolna, KOVÁCS Katalin, SZŰCS Miklós

[INTRODUCTION - Carcinomatous meningitis is a serious complication of advanced stage solid tumours, which may become more common with improved survival. CASE REPORTS - A 53-year-old woman with a recent history of breast cancer (pT2pN2M0) had been treated by mastectomy and adjuvant chemotherapy and radiotherapy. She presented with weakness, diplopia and vertigo raising the possibility of vertebrobasilar ischaemia or an intracranial mass. In another patient, a 62-year-old man with hypertension, a stenotic common bile duct had been diagnosed when examined for abdominal complaints. When he presented with a high blood pressure value accompanied by intensive headache, vomiting and bilateral hearing loss, he was thought to have a hypertensive crisis. The rapidly progressive neurological symptoms and the history of breast cancer and findings suggesting pancreatic head tumour, respectively, led to the clinical diagnosis of carcinomatous meningitis in both cases, despite any evidence on CT scans or a negative MR scan, though of limited value, in the first case. This diagnosis was confirmed by the laboratory and cytological findings of the cerebrospinal fluid, and also by the post mortem examination, since both patients died within a month after the onset of the symptoms. The primary tumour in the second patient proved to be a widely metastasizing diffuse type gastric cancer. CONCLUSION - Carcinomatous meningitis has a varying but characteristic presentation which generally makes it easy to diagnose, but it can sometimes present differential diagnostic problems. What we can learn from these two cases may help in recognizing this complication.]

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[Practical aspects of therapy by erythropoiesis stimulating agents in renal anaemia]

DEÁK György, HERSZÉNYI Eszter, AMBRUS Csaba, KISS István

[Prevalence of renal anaemia due to insufficient production of erythropoietin increases progressively in the course of renal function deterioration. Renal anaemia is treated by erythropoesis stimulating agents (ESA). Outcomes of randomized clinical trials have taught us to avoid the strategy of normalization of hemoglobin (HGB) levels by ESA therapy as it may increase the risk of cardiovascular events and mortality. The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anaemia published in 2012 recommends to start ESA therapy in the 90-100 g/l HGB range and suggests to keep HGB concentrations below 115 g/l. It is an inappropriate strategy to aim at normalizing hemoglobin (HGB) levels by ESA therapy because it may lead to progressive escalation of ESA doses even in the presence of diminished ESA responsiveness. High ESA doses and diseases causing ESA hyporesponsiveness eg. infections, chronic inflammation, malnutrition, insufficient dose of dialysis, severe hyperparathyroidism, iron deficiency are related to increased risk of mortality. KDIGO Clinical Practice Guideline for Anaemia emphasizes the importance of assessing and treating causes of ESA hyporesponsiveness, limits ESA dose escalation and recommends gradually changing ESA doses to avoid high amplitude HGB oscillation.]

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[Erythropoietin produced by the foetal liver and the adult kidney is the major stimulator of erythropoiesis. Erythropoietin production is regulated by hypoxic activation of erythropoietin gene transcription. Recently, new sites of erythropoietin production have been found mainly in the central nervous system and in the cardiovascular system. These tissues have a paracrine and/or autocrine system of erythopoietin. The pleiotropic function of erythropoietin in these systems is tissue and cell protection by several mechanisms including inhibition of apoptosis, attenuation of ischaemic or reperfusion injury, anti-inflammatory and antioxidative effects. Furthermore, it promotes vascular recovery and enhances neoangiogenesis. In vivo and in vitro studies have proved that systemically administered human erythropoietin can also provide tissue protection. However, adverse effects of erythropoietin treatment such as hypertension, hyperviscosity and thrombosis may override the beneficial effect of systemic erythropoietin treatment. There are preliminary data that erythropoietin analogues, e.g., asyaloerythropoietin or carbamylated erythropoietin can provide tissue protection without stimulating erythropoiesis.]

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[Anemia observed in patients with infectious, inflammatory, or neoplastic diseases and persisting for more than one month is called anemia of chronic disease. The term anemia of chronic disease is far from perfect, the terms of anemia of inflammation, cytokine-mediated anemia, and anemia of defective iron reuse are also used. Anemia of chronic disease is more common than any other anemia syndrome - apart from anemia caused by iron deficiency secondary to blood loss. Erythrocytes usually are normocytic, but hypochromia and microcytosis may also be observed. In almost every case, this type of anemia is hypo-regenerative. Characteristic laboratory findings include hypoferremia, hyperferritinemia, and hypotransferrinemia. Cause of this anemia is complex; pathogenesis of this anemia includes moderate shortening of erythrocyte survival, blunted response to erythropoietin, reduced medullar erythropoiesis, and limited medullar iron availability. In addition to treating the underlying pathology, treatment opportunities are recombinant human erythropoietin, transfusions, and intravenous iron.]

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[The authors sum up the physiology of erythropoiesis, the history of the erythropoietin’s discovery and the steps through which it became applicable to clinical adaptation. The biologically similar erythropoietin medicines and their application are reviewed. The setting of the target hemoglobin value and the weekly amount of erythropoietin needed for successful therapy are briefly surveyed. The authors draw attention to the fact that by increasing the dose the risk of mortality rises. Considering the other side effects they conclude based on international data and studies that “less is more” in this case namely the lower target value and erythropoietin dose can mean bigger therapeutic success. The erythropoietin treatment’s practice in Hungary is expressly efficient in the authors’ view.]


[Calcium supplementation and the risk of cardiovascular disease - Real apprehension or picking the spin?]


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