Observou-se um caso de resistência à eritropoetina recombinante humana causada por Ectasia Vascular Antral Gástrica em uma mulher de 40 anos de idade. Abstract. DAL MASO, Rosina Conceição Graçaplena et al. Sex hormones in women on dialysis. Rev. Assoc. Med. Bras. [online]. , vol, n.4, pp . 22 out. Observou-se um caso de resistência à eritropoetina recombinante humana causada por Ectasia Vascular Antral. Gástrica em uma mulher de.
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About 30 years ago, the treatment of chronic renal disease anaemia was revolutionized by the introduction of recombinant human erythropoietin, which reduced the need for blood transfusions.
In spite of this huge advance, the first recombinant human erythropoietin has a relatively short half-life and needs to be administered two to three times per week. Subsequently, other molecules were developed, such as darbepoetin alfa, continuous erythropoietin receptor activator CERA and peginesatide, with longer half-life, but the route of administration still remains a problem. Erythropoietin has an action that exceeds erythropoiesis and plays an important role in cell protection.
Based on knowledge of the molecular mechanisms that control erythropoiesis, namely the regulation of EPO gene expression, through HIF system, GATA-2 and NF-kB, several upcoming therapeutic agents and strategies for stimulating and treating anaemia emerged.
The humaha effort in developing these treatments is to achieve other routes of administration, recombibante convenient for the patient, such as oral therapy, not disregarding an easier production, storage and frequency of eritropoetiba.
In this work, based on a literature search of studies using MEDLINE, our objective is to review the regulation of erythropoietin production and its functions, as well as treatment approach for anaemia of chronic kidney disease, with particular focus on new therapies.
Anaemia; erythropoietin; GATA-2 inhibitors; hepcidin; hypoxia-inducible factors; kidney disease. Erythropoietin EPOformerly named haemopoietin is essential to erythropoiesis. Since its discovery, much has been achieved in the knowledge of the biology of this glycoprotein. Currently, decombinante know that EPO has an action that exceeds erythropoiesis and plays an important role in cell protection. Knowing that EPO has other functions, and also that regulators of the EPO gene are at the same time regulators of many other genes, we present a review on this issue.
We will mainly focus on EPO production, regulation and functions, taking also into account current therapies and new options for anaemia treatment. Erythropoietin is a hormone that controls erythrocytes production, promoting survival, differentiation and proliferation of erythroid progenitor cells in the bone marrow. Apoptosis prevention of these cells is the main mechanism underlying its function eritropoetkna.
The human EPO gene, located on chromosome 7 codes for EPO, a protein composed of amino acids, heavily glycosylated, with a molecular mass of about 30 kDa 2.
In adults, EPO is primarily synthesized in the kidney. Previous studies showed conflicting results about renal EPO-producing cells REPCbut the predominant location reported was the peritubular interstitial fibroblasts 3 and tubular epithelial cells, mainly present in renal cortex predominantly in the juxtamedullary region and in outer medulla.
InNagai et al. The production by peritubular cells occurred under hypoxic conditions, suggesting a different regulation mechanism between the nephrons and peritubular cells 5. During fetal life, EPO is produced by the liver. Similarly to the kidney, the liver responds to hypoxia increasing the number of EPO hepatocyte producers, located etitropoetina the central vein.
Erythropoietin was also found in liver eriropoetina cells, previously called Ito cells 6. In adult livers, EPO mRNA levels increase under moderate to severe hypoxia conditions, being one of the most important sources of extrarenal EPO, huana insufficient to normalize haemoglobin in chronic kidney disease CKD.
Apart from the kidney, EPO mRNA expression was also detected in non-haematopoietic tissues, such as brain neurons and glial cellslungs, heart, bone marrow, spleen, hair follicles, reproductive system, pancreatic islets and osteoblasts 7,8.
Under basal conditions, these cells do not play any role in erythropoiesis, but may contribute to induce stress erythropoiesis 9. In fact, EPO synthesized by these cells tends to act more locally, modulating, for example, regional angiogenesis and cell viability Erythropoietin is an endocrine, paracrine and autocrine hormone that acts as a cytoprotective hormone overextending its haematopoietic function.
Among other effects, EPO antagonizes the activity of proinflammatory cytokines, has neuroprotective functions and promotes healing through stimulation of angiogenesis and capillary growth, has direct effects on immune, endothelial and bone marrow stromal cells, as well as on heart, brain, reproductive system, gastrointestinal tract, muscle, eritroopetina, pancreas and nervous system cells 7. Erythropoietin acts co-ordinately at various levels, which includes: It has other non-erythropoietic biological functions, like mitogenesis and angiogenesis, in part via endothelin-1 induction.
Thus, anticipating an ischaemic insult for example, kidney recomninante or renal arteries clamping during abdominal surgeryrecombinant EPO can be used as a kidney tissue protector. Similarly, it may play humxna important role reducing CKD oxidative stress and vascular dysfunction. Erythropoietin prevents tubular epithelial cells apoptosis and stimulates surviving cell population mitotic activity In the central nervous system, EPO is involved in neuroprotection, neurogenesis and angiogenesis, playing an important function as a neurotropic and immunomodulatory factor Angiogenesis promotes neurovascularization, allowing ischaemic zone revascularization and increased oxygen supply.
Due to cell death reduction, eritropketina compensatory hypertrophic response and inflammation are attenuated, preventing a misfit remodelling In the skin, EPO enhances wound healing, reduces inflammatory response and increases capillary density in ischaemic regions. It also protects against diabetes in mouse models, mediated by Janus Kinase-2 JAK2 signalling directly in pancreatic cells, resulting gecombinante cell survival and proliferation, reduced inflammation and increased angiogenesis in the islets Erythropoietin may act on the regulation of metabolism and obesity and has potential benefits in the treatment of neurologic diseases, mood symptoms and depression Fig.
Therefore, EPO has an action that exceeds erythropoiesis and plays an important position in cell protection, using for that different cell receptors in erythropoiesis and cellular protection. Erythropoietin production is primarily stimulated by hypoxia and controlled transcriptionally.
According to hypoxia severity, serum levels can increase up to several hundred times. Hypoxia inducible factor HIF system: Thus, different intracellular pathways are activated: JAK2 activation also originates multiple binding sites for intracellular signalling proteins with src homology 2 SH2 domains 1.
In fact, the number of known genes activated by HIF continues to increase and includes genes whose proteins are involved in angiogenesis, energy metabolism, erythropoiesis, cell proliferation and viability, mitochondrial biogenesis, vascular remodelling and vasomotor responses Glycolytic enzymes induction demonstrates the role of HIF in the autonomous cellular adaptation to hypoxia, producing ATP by glycolysis, instead of oxidative phosphorylation.
The HIF activated genes are also involved in crucial aspects of cancer biology, such as angiogenesis, cell survival, glucose metabolism and invasion 21 and HIF regulated genes are induced when HIF heterodimers bind to specific DNA sequences and transcriptional cofactors are recruited. These sequences are found in regulatory regions of various genes, oxygen sensitive, and are called the hypoxia response elements HRE 2.
In normoxic conditions, HIF subunits are rapidly degraded by proteasomes, after binding with von Hippel-Lindau tumour suppressor VHLwhich is the recognition substrate of the ubiquitin E3 ligase complex that mediates the ubiquitination of HIF.
In hypoxic conditions, hydroxylation is inhibited and HIF signalling is activated. In fact, it is responsible for the prevention of erythroid progenitor cells apoptosis and the maintenance of a normal erythropoiesis, increasing erythrocytes production, under hypoxia The EPO production in the kidney and liver stimulates erythropoiesis and an additional need for iron that leads to an increase in intestinal iron absorption and iron binding capacity, as well as an increase in iron release from body iron stores.
It is a small peptide consisting of 25 amino acids, mainly produced by hepatocytes, whose transcription is sensitive to iron and oxygen. In addition to its antimicrobial properties, hepcidin controls the amount of iron absorbed in the duodenum and the release of iron from the recommbinante system cells such as Kupffer cells and splenic macrophages by ferroportin internalization and degradation, which is expressed in duodenal enterocytes, hepatocytes and macrophages Eritrppoetina hemojuvelin binds competitively to the BMP, which prevents the signalling of its receptor and suppresses hepcidin production Increased serum hepcidin levels were observed in chronic situations frequently associated with inflammatory conditions, which reduces recombinant expression and causes eritropoehina, supporting the key role of hepcidin in the pathogenesis of chronic disease anaemia A large proportion of CKD patients develop anaemia over the course of their disease, which is a risk factor associated with worse prognosis, either as an independent predictor factor or as a risk multiplier in patients with concomitant cardiovascular disease Anaemia severity is related to glomerular filtration loss degree, but independent of kidney disease aetiology.
The CKD anaemia is hypoproliferative and normocytic normochromic, unless recommbinante iron deficiency is overlapped. Although multifactorial haematinic deficiencies, shortened erythrocyte survival, low grade haemolysis, bleedingthe leading cause for CKD anaemia is the insufficient EPO production, due to decreased EPO gene expression The EPO gene activation in renal cells depends of microenvironmental signals and is not constitutively expressed, a possible reason why an adequate renal EPO-producing cell line is not available.
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Additionally, the uraemic environment associated with chronic inflammatory status contributes for erythrocyte survival decrease and erythropoiesis inhibition. These pro-inflammatory cytokines contribute to anaemia and EPO resistance. Furthermore, renal failure itself contributes to inflammation with an increase in advanced glycation end products AGEa reduction in plasma antioxidant activity and loss of antioxidants such as zinc, selenium and vitamins C and E. This inflammatory status leads to an increase in hepcidin release by the liver, with consequent serum ferritin increase and restriction on iron availability for erythropoiesis The fibrosis of bone marrow induced by secondary hyperparathyroidism can exacerbate the anaemia Until then, anaemic patients were primarily controlled with blood transfusions and, to a lesser extent, with anabolic steroids, both methods with severe limitations.
Regular transfusions increased the risk of infection, iron overload and anti-HLA human leukocyte antigen antibodies development, reducing the likelihood of a successful renal transplantation.
Steroid therapy, of limited efficacy, presented important side effects, such as hirsutism, virilization and hepatotoxicity, and was withdrawn Currently, the pharmacological treatment for anaemia in CKD includes therapy with erythropoiesis stimulating agents ESA and supplementation with iron. Erythropoiesis stimulating agents ESA: They are glycoproteins, manufactured by recombinant DNA technology, with the same biological activity as endogenous EPO.
In haemodialysis patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements and is the preferred administration route in pre-dialysis, transplant or peritoneal dialysis patients, for economic and practical reasons.
In CKD and cancer patients, this treatment is associated with an increased morbidity: The risk of death or cardiovascular events is associated with a poor initial haematopoietic response, with increased ESA doses to achieve the target haemoglobin levels Due to risk of tumour growth, rHu-EPO should be carefully evaluated in neoplasia setting.
Erythropoietin blocks tumour cells apoptosis and potentiates angiogenesis, with increased tumour growth, metastases and reduction of the radiotherapy response Hypertension and deep vein thrombosis incidence may also increase and antithrombotic prophylaxis in surgical patients treated with rHu-EPO should be considered Besides CKD anaemia, rHu-EPO is currently indicated for anaemia in patients undergoing elective surgeries and cancer patients with chemotherapyinduced anaemia to reduce blood transfusions The first available drugs were epoetin alfa and epoetin beta, two forms of recombinant EPO, both highly effective, but with a short duration of action administration 3 times a week: Ina second-generation ESA emerged: It is a hyperglycosylated EPO analogue with a higher number of sialic acid residues, which improves its biological potency.
Regarding the mechanism of action, it acts as the native EPO, stimulating its receptor. Due to its high metabolic stability, it has a greater half-life time compared to conventional EPO and may be administered once every two weeks Thus, it can be administered every two weeks or every month, during the maintenance phase of treatment Another of the agents approved by FDA was peginesatide, in Its advantages include low immunogenicity and easy production, without the need for cell cultures and genetic engineering techniques and, as CERA, peginesatide could be administered monthly.
However, since Marchthis treatment can only be given to patients on dialysis due to hypersensitivity reactions associated with injection, 0. The new erythropoietic stimulators, summarized in Table I.
Regulação da produção da eritropoietina e perspectivas terapêuticas na anemia
Apart from modulation of EPO gene, the modulation of hepcidin expression, involved in the genesis of anaemia and EPO resistance, has been actively searched. The EPO production is controlled by transcriptional and post-transcriptional oxygendependent mechanisms. Several HIF stabilizers compounds have been studied. One of the first candidates was FG, synthesized by FibroGen These agents have the advantage of being orally active, which represents a potential non-injectable therapy in the future.
Furthermore, they are able to modulate other genes involved in erythropoiesis, in particular those related with iron utilization: However, there are disadvantages to be mentioned: In addition, several hundreds of hypoxia sensitive genes are also activated by PHD inhibition, including those involved in glucose regulation, angiogenesis, etc.