EPO production

The primary cause of anemia in patients with CKD is a decrease in EPO production. With normal kidney function, as Hgb, hematocrit (Hct), and tissue oxygenation decrease, the... 

EPO was first used therapeutically in 1989 for the treatment of anaemia associated with chronic kidney failure. This anaemia is largely caused by insufficient endogenous EPO production by the diseased kidneys. Prior to EPO approval this condition could only be treated by direct blood transfusion. It responds well, and in a dose-dependent manner, to the administration of recombinant human EPO (rhEPO). The administration of EPO is effective, both in the case of patients receiving dialysis and those who have not yet received this treatment. 

The level of EPO production in the kidneys (or liver) is primarily regulated by the oxygen demand of the producer cells, relative to their oxygen supply. Under normal conditions, when the producer cells are supplied with adequate oxygen via the blood, EPO (or EPO mRNA) levels are barely detectable. However, the onset of hypoxia (a deficiency of oxygen in the tissues) results in a very rapid increase of EPO mRNA in producer cells. This is followed within 2 h by an increase in serum EPO levels. This process is prevented by inhibitors of RNA and protein synthesis, indicating that EPO is not stored in producer cells, but synthesized de novo when required. 

On the other hand, hyperoxic conditions (excess tissue oxygen levels) promote a decrease in EPO production. 

Table 6.6. Some additional regulatory factors that can promote increased EPO production. Other regulatory factors, including IL-3 and CSFs, which also influence the rate of erythropoiesis, are omitted as they have been discussed previously...

Suboptimal erythropoiesis can be classified by changes in the size of RBCs noted on examination of the peripheral blood. Because the excretory and endocrine functions of the kidney usually mirror each other, renal dysfunction can lead to anemia by reduction in EPO production, resulting in a normochromic, normocytic pattern. Other causes of insufficient erythropoiesis include replacement of bone marrow by fibrosis, solid tumors, or leukemia, as well as defects in erythroid maturation. Relative deficiencies in the cofactors required for heme-RBC synthesis such as iron, folate, and vitamin B may also be important contributors. Structurally, RBC macrocytosis denotes defects in the maturation of the nucleus, whereas microcytosis is indicative of cytoplasmic defects (reduced hemoglobin synthesis). (A detailed description regarding the pathogenesis and treatment of anemic disorders is found in Chap. 99.)... 

Anemia is a common complication in critically ill patients and is almost universally found in this patient population. Contributing factors include sepsis, frequent blood samples, surgical blood loss, immune-mediated functional iron deficiency, decreased erythropoietin (EPO) production, reduced RBC life span, and gastrointestinal bleeding. Low serum iron, TIBC, and a low iron TIBC ratio result. Serum ferritin is normal to high. The role of EPO in treatment is yet to be defined. 

Immunogenicity has attracted enormous attention recently, and this will be a key decision point for competitors to evaluate whether their molecule meets the criteria, or not. With regard to the reactions that may occur in products that are biotechno-logically driven, these results are not clearly understood. For example, changes in the manufacturing process may alter the nature of the finished product and trigger an immune response. A noteworthy case of this was centered on Johnson Johnson s EPO product which is currently marketed under the brand-name Eprex . 

It was shown that the chromatography method was suitable to separate recombinant EPO from amounts of human serum albumin commonly present as a stabilizer in various pharmaceutical preparations. In addition, it was possible to obtain different elution profiles for EPO products with variations in the glycoforms. Fluorescence detection was applied for quantification and showed linear signals over the range of 10-200-pg/mL EPO. 

Figure 4 Continuously generated H2O2 from glucose by glucose oxidase inhibits hypoxia-induced EPO production in HepG2 cells. H2O2 concentrations were calculated from the glucose concentration (5.5mmol/L) and the enzyme activity of the glucose oxidase. EPO protein was measured in the culture supernatant after a 24-hr h5poxic incubation.

Molidustat (BAY 85-3934) is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH), which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO [136]. Molidustat is currently under clinical trials at Bayer for the treatment of patients suffering from renal anemia due to chronic kidney disease. 

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