Quality of life improvements in dialysis patients receiving darbepoetin alfa

Short-acting hematopoietic agents can improve the quality of life (QOL) of hemodialysis patients, but questions remain regarding the domains of QOL affected, the relative importance of initial and final hemoglobin (Hb) concentrations, and the use of long-acting hematopoietic agents. We measured Hb concentrations and QOL in 487 hemodialysis patients who were switched from treatment with recombinant human erythropoietin to treatment with darbepoetin alfa. QOL was measured with the Japanese-language version of the SF-36, at the start of therapy with darbepoetin alfa and again 7-14 weeks later. We examined changes in QOL over time in the group as a whole, and in subgroups stratified by the change in Hb concentration. We also studied relationships between the final Hb concentration achieved and the magnitude of change in QOL. QOL scores increased significantly in all SF-36 domains except Social Functioning. The greatest increases were in vitality and in the two role-functioning domains. The magnitude of the increase in Hb concentration was related to the magnitude of the increase in QOL for only one subscale: Vitality. Patients with higher final Hb concentrations also had greater increases in Vitality scores. Hematopoiesis induced by darbepoetin alfa is associated with increased vitality and may also be associated with improved role functioning. Vitality increased significantly only in those patients with the greatest increases in Hb concentration and in those with higher final Hb concentrations.     

Treatment of renal anemia with darbepoetin alfa administered once every other week in predialysis patients with chronic kidney disease and previously treated with epoetin alfa

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein with up to 3 times longer half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to assess the efficacy and safety of darbepoetin alfa given once every other week as treatment of anemia in predialysis patients with chronic renal failure (CRF) previously treated with once-weekly epoetin alfa. A total of 42 CRF patients were included, all of whom had previously been treated with epoetin alfa and showed stable hemoglobin (Hb) levels without dose changes during the last 8 weeks prior to enrolment in this study. All patients received s.c. darbepoetin alfa once every other week at doses calculated from the protein mass equivalence between rHuEPO and darbepoetin alfa. Follow-up lasted for 24 weeks. Dose adjustments were conducted to preserve target Hb levels between 11 and 13 g/dl. Thirty-nine patients completed the 24 weeks of study. Hb levels increased during follow-up [mean values of 0.39 (p < 0.002), 0.58) (p < 0.001), and 0.83 g/dl (p < 0.001) at 8, 16 and 24 weeks, respectively] despite reducing the darbepoetin alfa dose up to 15% at 24 weeks [from 0.192 microg/kg body weight to 0.185, 0.178 and 0.163 at 8, 16, and 24 weeks, respectively (p < 0.001)]. No adverse events related to darbepoetin alfa were reported. In conclusion, these results show s.c. administration of darbepoetin alfa once every other week was superior to weekly epoetin alfa as a maintenance treatment for anemia in predialysis CRF patients, since the former provided higher Hb levels. Moreover, darbepoetin alfa administration was safe in these patients.     

Renal anemia - an important secondary disease in renal insufficiency

Anemia is as a frequent complication in patients with chronic kidney disease, which gains in importance in the treatment of patients with renal disease. The main cause of renal anemia is the inadequately low production of endogenous erythropoietin. Often the patients develop an additional absolute or functional iron deficiency, which complicates the diagnostic and therapeutic procedures. Substitution of recombinant human erythropoietin (r-HuEPO) is the most effective therapy. The goal is a stable haemoglobin level >11 g/dl. An often additional existing iron deficiency should be balanced adequately according to the guidelines. With consequent and early treatment morbidity, mortality, and quality of life can be effectively improved.     

An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis

OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). SUBJECTS: This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa. DESIGN: Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. RESULTS: The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects. CONCLUSION: Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.     

Pathophysiology and therapy of anemia in chronic renal insufficiency]

During a chronic renal insufficiency obligatorily an anaemia develops, which shows a statistically highly significant non-linear correlation to the degree of the impairment of the renal function. The pathogenetic points of view are very diverse and include disturbances of the formation of erythrocytes and a shortened life span of the erythrocytes. The necessary treatment of anaemia, above all in patients on the chronic dialysis programmes must consider these pathomechanisms and will be in most cases identical with a polypragmasy.     

Treatment of chronic renal insufficiency in the diabetic by dialysis and transplantation

The number of diabetics with end stage renal disease (ESRD) is growing. The best treatment at the lowest cost possible should be offered to all diabetics if therapeutic facilities are available. Such a policy requires that all dialysis methods and transplantation should be available and that transfer from one method to another should always be allowable. Results observed among insulin and non insulin-dependent diabetics are improving steadily, even in the older age group. However they are inferior to those observed in non diabetic people of the same age. Adequate medical care, including excellent control of high blood pressure and good control of blood glucose levels should reduce the frequency of severe complications including cardiac, ocular and peripheral vascular lesions. In diabetic patients under forty years of age, renal transplantation using a kidney from a cadaver or a related donor should be the first choice. However, for most patients dialysis methods are required as the only treatment or while waiting for a transplant. Very encouraging results are obtained with both hemodialysis and peritoneal dialysis. If home dialysis is considered, continuous ambulatory peritoneal dialysis (CAPD) offers the opportunity to treat many insulin-dependent or non dependent diabetics at home even those in the high risk population because of age and/or cardio-vascular instability. CAPD offers excellent control of blood glucose levels using the intraperitoneal route to administer insulin. Results obtained are discussed from data in the literature and from a survey of 124 insulin-dependent diabetic cases with ESRD treated in the Department of Nephrology of the Hospital de La Pitié from 1973 to 1984.     

Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model

OBJECTIVE: We developed a rodent model of noninfectious systemic inflammation to examine the pathogenesis of the associated anemia of chronic disorders (ACD), to evaluate the similarity of this ACD model to human ACD, and to evaluate the potential efficacy of novel erythropoiesis stimulating protein (darbepoetin alfa) as an ACD therapy. METHODS: Lewis rats were immunized with peptidoglycan-polysaccharide polymers (PG-APS), the chronic inflammation and associated ACD were characterized, and the effects of darbepoetin alfa treatment on complete blood counts (CBC), red blood cell (RBC) indices, and iron metabolism were analyzed weekly. RESULTS: Acutely inflamed rats had reduced peripheral blood (PB) RBC counts and hemoglobin (Hb) concentrations and increased reticulocyte counts. PB RBC numbers normalized during chronic inflammation, but RBC remained hypochromic and microcytic. Consequently, the rats remained chronically anemic. Anemic rats had fluctuating serum erythropoietin (EPO) concentrations, but mean EPO concentrations never varied significantly from baseline control levels. Histology of anemic rat spleen sections revealed reticuloendothelial siderosis. Total serum iron concentrations were chronically low. Peritoneal exudate cells (PEC) isolated from anemic rats and stimulated with PG-APS in vitro produced more interleukin (IL)-1alpha and interferon (IFN)-gamma, and significantly more tumor necrosis factor (TNF)-alpha and IL-10 than control cultures. Darbepoetin alfa restored Hb concentrations to baseline levels within 2 to 7 weeks, depending on dosage. A refined treatment strategy restored Hb to baseline and maintained those levels with reduced dosing. CONCLUSION: ACD in this rodent model closely replicates human ACD. Darbepoetin alfa treatment reversed ACD in this model by increasing RBC production and RBC hemoglobinization while reducing siderosis and hypoferremia.     

Importance of ultrapure dialysis liquid in response to the treatment of renal anaemia with darbepoetin in patients receiving haemodialysis

Chronic inflammatory diseases and infections are a major cause of hyporesponse to erythropoiesis-stimulating factors. We conducted this prospective study in 107 patients in haemodialysis with dialysis liquid that was potentially contaminated from a bacteriological perspective in order to test the hypothesis that ultrapure dialysis liquid can improve the response to treatment with darbepoetin and reduce inflammatory markers. These patients had to have been stable in the last 8 weeks in relation to haemoglobin level and the administered dose of darbepoetin. Two filters (one of hydrophilic nylon and another of polysulfone) were added to the water treatment process, the first one prior to distribution ring output and the second before the dialyser. The patients were evaluated for 12 months. The dosage of darbepoetin was varied to maintain haemoglobin levels ranging from 11 to 14 g/dl. We measured resistance to the erythropoiesis-stimulating factor, defined as the quotient between weekly dose of darbepoetin and haemoglobin levels, baseline and every two months, the baseline and monthly endotoxin count and reactive protein C at baseline and every 6 months. 94 patients completed the study. The resistance index fell significantly during follow-up (p<0.001) and was measurable from the second month on. Haemoglobin levels remained within the established margins with a 34% reduction in the weekly dose of darbepoetin at the end of the follow-up period. Both reactive protein C and the endotoxin count were significantly reduced (p<0.001) compared to baseline after 6 and 12 months. To conclude, the bacteriological purity of the dialysis liquid reduces inflammatory markers in patients receiving haemodialysis, improving the response to treatment with darbepoetin in renal anaemia.     

Acute renal insufficiency secondary to interferon

Alpha interferon is increasingly used in the treatment of malignancies and viral hepatitis. Renal involvement after its use consist in more cases on proteinuria. We report one case of acute renal failure without nephrotic syndrome but with tubulointerstitiel infiltration by mononuclear cells in 65 old man who had before interferon therapy 151 mumol/l of serum creatinine. Interferon was administrated for digestive carcinoid neoplasia and bone and liver metastasis. Outcome was improvement of renal function after withdrawn of interferon, dialysis and steroid treatment.     

Effect of darbepoetin alfa on endothelial progenitor cells and vascular reactivity in chronic kidney disease

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.