Hypertension and nephrology

[Goals, doubts and confidences in treatment of renal anemia]

KISS István, SZEGEDI János, KULCSÁR Imre, DEÁK György, KISS Zoltán, REMPORT Ádám, AMBRUS Csaba

JULY 20, 2013

Hypertension and nephrology - 2013;17(02)

[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.]

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[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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[Oxidative stress plays an important role in the elevation of the cardiovascular risk of patients with chronic kidney insufficiency. The oxidative stress becomes more severe together with the deterioration of the renal function, and the hemodialysis sessions may also induce repetitive oxidative insults. Erythropoesis-stimulating agents (ESAs) may alter the level of oxidative stress via their effects on hematopoiesis, resulting in indirect effects on changes of iron metabolism and the levels of antioxidants. We review the current knowledge about the administration of ESAs as concerns effects on oxidative parameters in hemodialysis patients. We discuss the relationship between the characteristics of the ESA therapy (type, administration frequency and dosage of ESA, length of the therapy, administration withdrawal) and the oxidative stress in view of earlier and recent research.]

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[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.]

Hypertension and nephrology

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[The original patent drugs appear immediately on expiry of all rights in generic and biosimilar drugs in the pharmaceutical market, favorable supply option which helps in the rational management of medicines, mainly for generic drugs cheaper to allow more patient care. Of course, this is a well-organized legal and regulatory framework, thoughtful strategy can be successful in every respect. In another non-identical molecular structure biosimilar drugs in different immunogenicity of knowledge and risk is not defined in clinical practice and therefore the risk is still underestimated and not well regulated in the world, and increasing the number reported is the antibody formation case of a biosimilar erythropioetin also. The immunogenicity of original biological and of biosimilar drugs in identifying, defining a prominent role in the post-marketing surveillance, pharmacovigilance, and the special methods of control of immunogenicity. The original and the biosimilar medicines interchangeability, marketability of the assets relating to the regulations are not uniform in Europe or the European registration scheme is an important new biosimilar medicinal products, is that the medicinal product, the documentation is not expected to be accompanied by a risk management plan, as well as action to ensure the safety (pharmacovigilance) as part of the collection and reporting of adverse reactions to the official. It is important that the professional management of renal anemia guidelines - the practice of nephrology erythropoietin therapy - clearly define the biological medicines (originator and biosimilar erythropoietin) application requirements and suggestions. Consequently, this summary wants to draw attention to the therapeutic potential of biosimilar drugs, generic drugs to distinguish between explicit and the potential risks and the need to reduce the risks of professional and health policy decisions.]

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[Biosimilar erythropoietins in nephrology - benedictio seu maledictio?]

KISS István

[Biological medicines of protein or polypeptide origin produced with biotechnology are far more complex in structure than the low molecular weight chemical ones. In conjunction with chemical drugs generic copies are completely the same, while in the field of biological medicines only similarity can be stated, as identical molecules cannot be produced. Spatial structure, isomers and side chains cause difference and for this reason these are called biosimilar drugs. Immunogenity of biosimilar drugs is very different and the risk of antibody production against them is diverse. Pure red cell aplasia, a rare side effect of erythropoietins is a life-threatening condition so every effort must be done for its prevention. Biosimilar drugs are not to be replaced with each other, and even the reference drugs should not be substituted in order to identify easily the side effects of each drug. Importantly financing should support these clinical principles namely a cheaper drug could be started as a new treatment but a former treatment should not be replaced because of cost sensitivity. It is important to provide the availability of the very expensive biologically active drugs to each patient but it is acceptable that the treatment should be as cost-effective as possible. Similarly to the generic copy program of chemical drugs biosimilar drugs are also important for the clinical practice, however their use needs appropriate regulation and farmacovigilance.]