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Chronic kidney disease leads to dysfunction of renal erythropoietin-producing cells, resulting in a decrease in erythrocyte production. A decrease in oxygen delivery to vital organs due to anemia results in worse quality of life and is associated with poor prognosis of the patients. Treatment with human recombinant erythropoietin or its improved version of erythropoiesis-stimulating agent (ESA) with a longer half-life is effective. However, some patients show hyporesponsiveness to ESA. Hyporesponsiveness to ESA, which can be induced by factors such as inflammation and uremic toxins, is associated with poor prognosis. Production of erythropoietin in the kidney is regulated by a transcription factor, hypoxia-inducible factor (HIF). PHD regulates HIF activity, and recently developed PHD inhibitors need to be clinically used as drugs to ameliorate anemia in CKD by activating HIF.

Cancer chemotherapy-induced anemia(CIA)is observed in approximately 70%of patients treated with cytotoxic chemo- therapy. The hemoglobin concentration in the peripheral blood is C10 g/dL in 40% of these patients, and C8 g/dL in 23% of these patients. Red blood cell transfusion is performed in 16% of these patients. Since erythropoiesis-stimulating agents (ESA)are not approved in Japan, blood transfusion is the only choice of treatment for CIA. In Northwestern countries, ESA have been utilized for the treatment of CIA for >20 years. Recently, however, the use of ESA has become regulated towing to concerns about the potential life-shortening effects, although ESA are still the treatment of choice for CIA. In this paper, the characteristics of CIA in Japan and the underlying issues have been discussed.

The prognosis of cancer patients with anemia is poor. In Japan, these patients are treated only with red blood cell transfusions, and doctors cannot use erythropoiesis stimulating agents(ESAs)such as epoetin and darbepoetin. On the other hand, ESAs are widely used in the USA and Europe to treat patients with chemotherapy-induced anemia. However, the results of randomized controlled trials(RCTs)and meta-analysis have suggested that the use of ESAs was correlated with increasing incidence of venous thromboembolism(VTE)and mortality. The American Society of Clinical Oncology(ASCO)and the American Society of Hematology(ASH)guidelines, revised in 2010, recommend the minimal use of ESAs for patients with chemotherapy-induced anemia, except for anemic cancer patients who are not currently receiving chemotherapy. A change in the target hemoglobin(Hb)level to achieve a concentration of 12 g/dL was recommended in 2007 as the lowest concentration required to avoid transfusions. We discuss the cause of anemia in cancer patients, and examine the current state of the clinical use and problems associated with ESAs.

Chronic kidney disease (CKD) is now recognized as a risk factor of both end-stage renal disease (ESRD) and independently cardiovascular disease (CVD). Therefore, a specific renoprotective intervention is strongly recommended, including blood pressure control as well as anemia improvement with erythropoietin stimulating agents (ESAs). Treatment of renal anemia with ESAs has been proved to improve quality of life (QOL) and finally reduce patient mortality. Recently, Silverberg, et al. created a novel clinical entity of Cardio-Renal Anemia (CRA) syndrome, in which anemia plays a key role for worsening both CKD and cardiac performance in a vicious circle. An appropriate and vigorous treatment of anemia has now been accepted to terminate or weaken the circle. Recently, two large-scaled randomized controlled trials were reported, being the CREATE (cardiovascular risk reduction by early anemia treatment with epoetin beta) study and the CHOIR (correction of hemoglobin and outcomes in renal insufficiency) study. They demonstrated that early initiation of ESA treatment and targeting at higher hemoglobin level (near normal level) failed to show the lowering effects for cardiovascular events as compared to a group in which Hb targeting was lower (sub-normal level) in pre-dialysis CKD patients. While there has been many argues in these reports especially about baseline patients characteristics, being a quite high incidence of severe cardiovascular co-morbidity. Thus, further evidences should be accumulated to resolve a proper target level of Hb in ESA treatment.

Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. However, in Japan, only iron supplementation and blood transfusion were available for the treatment of anemia with cancer. On the other hand, in Europe and America, erythropoietic agents such as erythropoietin and novel erythropoiesis stimulating protein (NESP) have been clinically used for anemia in patients with cancer.

For cancer treatment-related anemia, it is recommended to use erythropoietin or darbepoetin alpha by the National Comprehensive Cancer Network (NCCN). The guideline proposed the risk assessment for anemia, as well. The introduction of erythropoietin or darbepoetin alpha for anemia in treated cancer patients is based on the improvement of quality of life. For patients with myelodysplastic syndrome (MDS), those with 5q- anomaly is recommended to use lenalidomide and low-risk MDS patients without 5q- and serum erythropoietin of less than 500 mU/ml are recommended to treat with erythropoietin or darbepoetin alpha. These new agents are currently under clinical trials in Japan.

Objective: The SF-36v2 (version 2 of the SF-36 health survey) is an instrument used worldwide to measure the generic health-related quality of life (HQOL). The SF-36v2 has "standard" and "acute" forms, in which respondents are asked about the previous month and the previous week, respectively. The standard form of the Japanese-language version of the SF-36v2 has already been validated, but the acute form has not. We evaluated the validity and reliability of the Japanese SF-36v2 acute form in patients with chronic kidney disease (CKD)., Methods: Cross-sectional data from 210 CKD patients who enrolled a clinical trial of a long-acting erythropoiesis stimulating agent (darbepoetin alfa) were analyzed. The feasibility of question items and distributions of the response choices were examined. Cronbach's alpha was computed to assess internal-consistency reliability. Construct validity was evaluated with tests of convergent and discriminant validity, and with factor analysis. Validity with regard to reference groups for the severity of anemia and for performance states was also assessed., Results: There were few missing data and the distribution of response choices did not differ between the acute form and the standard form. Values of Cronbach's alpha for the acute form sub-scales were sufficient. The percentages of items that passed the tests of convergent validity and discriminant validity were 100% and 98.7%, respectively. Factor analysis identified the same components in the acute form as in the standard form. "Dose-response" relationships were found between the sub-scale scores on the acute form and the severity of anemia, and also between those scores and performance states., Conclusions: The Japanese SF-36v2 acute form can be expected to provide valid and reliable HQOL data in CKD patients.

Patients with cancer-related anemia have an inadequate Epo response that is further impaired by cancer treatments such as chemotherapy. Significant number of studies have demonstrated that treatment of anemia in cancer patients using recombinant human EPO(rHuEPO, epoetin alfa) significantly increases hemoglobin(Hb) levels,reduces transfusion requirements,and improves quality of life,particularly by relieving fatigue. However,the findings of several studies have raised the possibility of an adverse effect of thromboembolism. The American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. In cancer patients, the risk of bleeding depends not only on the platelet count, but also on the underlying disease, in accordance with coagulation defects. The cause of thrombocytopenia must be established prior to platelet transfusion since platelet transfusions may be relatively contraindicated in certain conditions e. g., heparin-induced thrombocytopenia(HIT), and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome(TTP/HUS).