Production erythropoietin

The most common complication of CKD is anemia, which is caused by a decline in erythropoietin production by the kidneys and can lead to cardiovascular disease. 

Patients with CKD suffer from a decrease in erythropoietin production because erythropoietin is produced mainly in the kidneys.4,5 Finally, in patients with anemia of chronic disease, there is a blunted erythropoietin production as well as a diminished response to erythropoietin.9 Anemia of chronic disease also affects iron homeostasis, causing iron sequestration into storage sites and decreasing the amount available to the rest of the body.9... 

Parenteral iron therapy currently is available in three different formulations, which are listed in Table 63-3. Iron dex-tran was the first parenteral iron formulation to be approved, followed by ferric gluconate, and then iron sucrose. Although these newer agents are only approved by the Food and Drug Administration (FDA) to treat anemia associated with CKD in patients receiving erythropoietin products, they are effective in treating iron-deficiency anemia as well. Iron dextran is FDA approved for treating documented iron deficiency in patients who are unable to tolerate the oral formulation. 

Studies have shown that in patients with chemotherapy-related anemia, therapy with erythropoietin products (epoetin-alfa and darbepoetin) can increase hemoglobin, decrease transfusion requirements, and improve quality of life.12 Epoetin is recombinant human erythropoietin, and darbepoetin is structurally similar to endogenous erythropoietin. Both bind to the same receptor to stimulate red blood cell production. Darbepoetin differs from epoetin in that it is a glycosylated form and exhibits a longer half-life in the body. The half-lives of a single subcutaneous injection of epoetin or darbepoetin in patients are roughly 27 and 43 hours, respectively. 

The response to erythropoietin products must be monitored closely to prevent adverse effects associated with these agents. The common adverse effects experienced include hypertension and thrombosis. Concomitant drugs with the same adverse-effect profile may increase a patient s risk for these complications. Also, the patient s overall survival may be decreased if the hemoglobin level is titrated to above the recommended 11 to 12 g/dL (110-120 g/L or 6.82-7.44 mmol/L) value. Therefore, it is important to follow the dosing and titration scheme recommended by the NCCN and summarized in... 

Cancer patients also may have concurrent iron deficiency secondary to erythropoietin use ( functional iron deficiency) or to cancer. Therefore, it is imperative that these patients have iron studies done to assess adequate iron stores needed to drive hematopoiesis. If the patient is determined to have sub-optimal iron stores or is iron deficient, then replacement either orally or intravenously may be necessary, in addition to the use of erythropoietin products. The use of iron in these patients is the same as discussed previously under Iron-Deficiency Anemia. ... 

TABLE 63-4. Erythropoietin Products and Their Usual Doses for Anemia from Cancer/Chemotherapy and CKD... 

Do not exceed more than 1 g/dL (10 g/L or 0.62 mmol/L) every 2 weeks when using erythropoietin products to increase hemoglobin. Otherwise, decrease the dose of the erythropoietin product. 

When initiating erythropoietin products, assess the patient s iron status. 

Erythropoietin products hypertension (monitor blood pressure), thrombosis (e.g., DVT/PE, Ml, CVA, and TIA), arthralgias, and headache... 

Anemia of chronic kidney disease A decline in red blood cell production caused by a decrease in erythropoietin production by the progenitor cells of the kidney. As kidney function declines in chronic kidney disease, erythropoietin production also declines, resulting in decreased red blood cell production. Other contributing factors include iron deficiency and decreased red blood cell lifespan, caused by uremia. 

Liebelt E Yale University, New Haven, CT Investigate whether children with lead poisoning have lower erythropoietin production compared to children without lead poisoning determine if there is a threshold for diminished erythropoietin production in children with lead poisoning National Center For Research Resources... 

Ongoing studies regarding analytical methods for lead were reported in the Federal Research in Progress File (FEDRIP 1998) database. Only one had relevance to analytical methods and was related to biomarkers. Dr. Liebelt at Yale University, with funding from the National Center for Research Resources, is investigating erythropoietin production in children with lead poisoning. 

Pharmacology Erythropoietin is a glycoprotein that stimulates red blood cell production. It is produced in the kidney and stimulates the division and differentiation of erythroid progenitors in bone marrow. Hypoxia and anemia generally increase the production of erythropoietin, which in turn stimulates erythropoiesis. In patients with CRF, erythropoietin production is impaired this deficiency is the primary cause of their anemia. Epoetin alfa stimulates erythropoiesis in anemic patients on dialysis and those who do not require regular dialysis. 

Carboxyhemoglobinaemia Chronic obstructive airways disease Pulmonary hypoventilation syndrome Right-to-left cardiac shunt Absolute - physiologically inappropriate Ectopic erythropoietin production Renal carcinoma and cysts Hepatoma... 

Therapy in those with ectopic erythropoietin production depends upon correcting the hormone level by removing whatever tissue is responsible for its production and examples include nephrectomy for renal carcinoma or the classical, albeit rare, cerebellar haemangioblastoma. Where metastases have occurred appropriate cytotoxic chemotherapy is needed and response in haematocrit becomes a rough indicator of the success with which the tumour is responding to therapy. In some individuals venesections are necessary to control the raised haemoglobin. 

Abnormalities of liver function tests are occasionally seen, as is a varying degree of anemia due to reduced erythropoietin production by damaged renal tubular cells. After intrathecal therapy with amphotericin, seizures and a chemical arachnoiditis may develop, often with serious neurologic sequelae. 

Rizzuto, G., Cappelletti, M., Maione, D., Savino, R., Lazzaro, D., Ciliberto, G. et al. (1999) Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation. Proc. Natl. Acad. Sci. USA, 96, 6417-6422. 

Yang M, Butler M (2000), Effects of ammonia on CHO cell growth, erythropoietin production and glycosylation, Biotechnol. Bioeng. 68 370-380. 

Wang MD, Yang M, Huzel N, Butler M (2002), Erythropoietin production from CHO cells grown by continuous culture in a fluidized-bed bioreactor, Biotechnol. Bioeng. 77 194-203. 

Klausen, T., The feed-back regulation of erythropoietin production in healthy humans, Danish Medical Bulletin, Vol. 45, No. 4, 1998, pp. 345-53. 

Stockelman et al. (1998) described chronic renal failure in a mouse model of human adenine phospho-ribo-syltransferase deficiency. Hamilton and Cotes (1994) used a partial nephrectomy model in mice with two-thirds of the total renal mass excised to evaluate erythropoiesis and erythropoietin production from extrarenal sources such as the submandibulary salivary gland. Koumegawa et al. (1991) suggested the DBA/2FG-pcy mouse, which develops numerous cysts in kidney cortex and medulla, a progressive anemia and an elevation of blood urea nitrogen, as a useful spontaneous model of progressive renal failure. 

Q5 The term haematocrit refers to the percentage of total blood volume occupied by packed red blood cells (erythrocytes). In males the haematocrit is normally 40-54% Chandra s packed cell volume is higher than normal 59%. Development of erythrocytes takes place in red bone marrow and is controlled by the hormone erythropoietin, which is produced by kidney cells. The major stimulus for erythropoietin production and release is hypoxia. 

Japanese volunteers (36). The analysis estimated the population mean values of k, kg, and the endogenous erythropoietin production rate to be 0.043 hr / 0.206 hr 3.14 and 15.7 lU hr respectively. The good correlation between predicted and observed concentration values shown in Figure 32.13 supports the choice of models as does the fact that the values for ke and determined by this analysis were similar to those reported for intravenous erythropoietin with the standard two-stage method of determining population PK parameters (see Chapter 10). However, given the flip-flop PK characteristics of erythropoietin (Table 32.10), the comparison to the IV parameter estimates may be misleading. In fact, the values for kg estimated by the population PK are dissimilar to those obtained by other authors after SC administration of erythropoietin (25). 

Worldwide, 112 cases of pure red cell aplasia have been reported after subcutaneous administration of epoetin alfa (especially Eprex) in patients with chronic renal insufficiency. In these patients, neutralizing anti-eiythropoietin antibodies were detected (82-84) these antibodies cross-react with all other erythropoietin products. This adverse... 

Sakaguchi M, Kaneda H, Inouye S. A case of anaphylaxis to gelatin included in erythropoietin products. J Allergy Clin Immunol 1999 103(2 Pt l) 349-50. 

Human recombinant erythropoietin (rhEPO or epoetin) is is a synthetic version of human EPO that is used to treat anemia. Following replenished iron stores and exclusion of other causes of anemia, the addition of recombinant epoetin is indicated for the treatment of CKD-related anemia. The gene for human EPO was cloned in 1985 and epoetin was introduced into clinical practice shortly afterwards.It is effective at correcting the anemia of CKD in 90% to 95% of patients. The most common side effect is hypertension and therefore blood pressure should be well controlled before the introduction of treatment. Hypertension may develop or worsen in 23% of patients. Failure to respond to treatment requires thorough investigation for many potential causes (Box 45-2). It is estimated that 3 million patients worldwide have received treatment with epoetin. Pure red cell aplasia (PRCA) has occurred in patients treated with epoetin. This has been described in a small number of patients receiving epoetin via the subcutaneous route. In the majority of cases, neutralizing antibodies to EPO have been detected. If a case of PRCA is proven, then no further recombinant erythropoietin products can be administered. 

Polycythemia is characterized by an increase in the number, and in the hemoglobin content, of circulating red cells. In patients who have chronic anoxia from impaired pulmonary ventilation or congenital or acquired heart disease, the increase in plasma erythropoietin leads to secondary polycythemia. Some renal cell carcinomas, hepatocarcinomas, and other tumors, which produce physiologically inappropriate amounts of erythropoietin, may also cause secondary polycythemia. Conversely, anemia can result from renal insufficiency and from chronic disorders that depress erythropoietin production. In polycythemia vera (primary polycythemia), which is a malignancy of erythrocyte stem cells of unknown cause, erythropoietin levels are normal or depressed. 

Fandrey J, Frede S, Ehleben W, Porwol T, Acker H, et al. 1997. Cobalt chloride and desferrioxamine antagonize the inhibition of erythropoietin production by reactive oxygen species. Kidney Int 51 492-496. 

Fandrey J, Frede S, Jelkmann W. 1994. Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem J 303 507-510. 

S. Masuda, M. Okano, K. Yamagishi, M. Nagao, M. Ueda, and R. Sasaki, A novel site of erythropoietin production, oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269 19488-19493 (1994). 

Most patients who require dialysis have a normocytic normochronic anemia and a hypoproliferative bone marrow. As erythropoiesis decreases with advancing renal disease, iron shifts from circulating red cells to the reticuloendothelial system, leading to high serum ferritin levels. Repeated blood transfusion is also a common cause of iron overload and hyperferritinemia. Clearly the most important cause of the anemia of chronic renal failure is decreased erythropoietin production by the kidneys uremic patients have much lower plasma erythropoietin levels than comparably anemic patients with normal renal function (E8). Less important causes are shortened red cell survival, iron or folate deficiency, aluminum intoxication, and osteitis fibrosa cystica (E8). Uremic retention products such as methylguanidine (G10) and spermidine (R2) may also have an adverse effect on erythropoiesis. 

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