Treatment of the anemia of hemodialysis patients with recombinant human erythropoietin

Fifteen long-term hemodialysis patients suffering from stable anemia received recombinant human erythropoietin (r-huEPO). The hormone was given intravenously at the end of each dialysis session starting with a dose of 24 IU/kg. This dose was doubled when hemoglobin levels did not rise within 2 weeks. The number of reticulocytes started to increase after 14 days of treatment. The hematocrit rose from baseline values of 23.7 +/- 1.2% to 32.4 +/- 1.3% after 24 weeks of treatment. In parallel, hemoglobin values increased from 7.3 +/- 0.3 g/100 ml to 10.1 +/- 0.4 g/100 ml. As for side effects, 3 patients developed hypertension and 2 patients suffered from occlusions of their arterio-venous fistulas. There was no evidence of major organ dysfunctions, toxic effects, allergic reactions, or antibody formation. These data show that r-HuEPO is able to correct the anemia of patients undergoing hemodialysis treatment.     

Use of hemodialysis equipment in diagnosis of calcium metabolism disorders in patients with terminal chronic renal insufficiency

Research Institute of Transplantology and Artificial Organs, Ministry of Health of the USSR Moscow. Translated from Meditsinskaya Tekhnika, No. 1, pp. 27–29, January–February, 1991.     

Use of neural networks for dosage individualisation of erythropoietin in patients with secondary anemia to chronic renal failure

The external administration of recombinant human erythropoietin is the chosen treatment for those patients with secondary anemia due to chronic renal failure undergoing periodic hemodialysis. The goal is to carry out an individualised prediction of the erythropoietin dosage to be administered. It is justified because of the high cost of this medication, its secondary effects and the phenomenon of potential resistance which some individuals suffer.One hundred and ten patients were included in this study and several factors were collected in order to develop the neural models. Since the results obtained were excellent, an easy-to-use decision-aid computer application was implemented.     

Erythrocyte metabolism during renal anemia treatment with recombinant human erythropoietin

Recombinant human erythropoietin (epoetin) is widely used for the treatment of renal anemia. The aim of our study was to determine the influence of epoetin on erythrocyte metabolism. Thirty-six hemodialysis patients (22 men, 14 female), aged from 17 to 64 years (mean age 43) and 30 healthy volunteers (12 men, 18 female), aged from 25 to 65 years (mean age 40) were studied. Epoetin (Eprex, Janssen-Cilag) was administered subcutaneously with the starting dose of 2000 IU three times per week for twelve months (range from 75 to 133 IU/kg/week, mean dose 102+/-21 IU/kg/week). Laboratory markers of: hematological response, iron status and erythrocyte metabolism were measured before epoetin administration. Afterwards the markers were controlled every three months. During epoetin treatment a significant increase in hemoglobin concentration was observed (100% patients responded in a positive way to epoetin). The following changes in erythrocyte metabolism were noticed: 1) in glycolytic enzymes: a significant increase in the activity of hexokinase and that of lactate dehydrogenase, 2) in glycolytic intermediates: a significant increase in the 2,3-diphosphoglycerate and adenosine triphosphate concentrations, 3) a significant increase sodium, potassium adenosine triphosphatase concentration, 4) the glucose uptake by erythrocytes significantly decreased while the lactate production remained stable. During anemia treatment with epoetin in hemodialysis patients not only quantitative but also qualitative changes in erythrocytes were observed.     

Treatment of the anemia of progressive renal failure with recombinant human erythropoietin

To examine the effects of erythropoietin on the anemia of chronic renal disease and on the rate of renal deterioration, we administered recombinant human erythropoietin to 17 patients with anemia and progressive renal failure who did not yet require dialysis (serum creatinine level, 353 to 972 mumol per liter [4.0 to 11.0 mg per deciliter]). The dose of erythropoietin (50 to 150 units per kilogram of body weight) was adjusted according to the hematocrit response. In all 17 patients the anemia responded to erythropoietin. The median hematocrit increased from 0.27 to 0.37. The rate of the response depended on the initial erythropoietin dose and was similar to that observed in patients who were on dialysis. Hypertension was present in 14 patients before therapy, developed during therapy in 2 of the normotensive patients, and worsened in 9 patients, who required additional antihypertensive medications. The rate of the decline in renal function, as measured by serial determination of the reciprocal of the serum creatinine level, did not change significantly as the hematocrit rose (P = 0.78 by the paired t-test) during erythropoietin therapy. All the patients reported improvements in appetite, activity level, and sense of well-being. We conclude that erythropoietin therapy is effective in correcting the anemia of patients with progressive renal failure without affecting renal function, although it may be associated with an increase in blood pressure.     

Normalization of serum prolactin levels in hemodialysis patients on recombinant human erythropoietin

Correction of anemia in long-term hemodialysis patients by recombinant human erythropoietin (r-HuEPO) has been reported to improve sexual function. As elevated serum prolactin levels are believed to contribute to altered sexual function in uremia, we followed serum prolactin and testosterone levels during four months of r-HuEPO therapy. Within these four months, hematocrit values rose from 23.7 +/- 1.2 to 35.7 +/- 0.2% and hemoglobin from 7.3 +/- 0.3 to 11.3 +/- 0.4 g/100 ml. In parallel, serum prolactin values decreased significantly, from 66.9 +/- 9.3 to 9.6 +/- 2.6 ng/ml in females and from 39.5 +/- 10.5 to 10.3 +/- 1.0 ng/ml in male dialysis patients. Testosterone concentrations were in the lower normal range in male patients and remained unchanged during r-HuEPO therapy. Sexual function improved in four out of seven males, and five out of nine female patients started to have regular menstruations again. It appears that treatment of anemia in end-stage renal disease by r-HuEPO may improve sexual function by lowering elevated serum prolactin concentrations.     

Lymphocyte subsets in hemodialysis patients treated with recombinant human erythropoietin

We investigated whether recombinant human erythropoietin (rhEPO) therapy affected the lymphocyte subsets in patients on long-term maintenance hemodialysis (HD) with severe anemia. Before treatment, the numbers of peripheral blood lymphocyte, CD3⁺, CD4⁺, CD8⁺, and CD20⁺ cells were decreased in HD patients compared to those in healthy subjects, while the number of CD3⁺ HLA-DR⁺ cells was increased in HD patients compared to that in healthy subjects. Furthermore, the number of CD4⁺CD45RA⁺ (naive T) cells was markedly decreased in HD patients (112±77 vs 241±146/µl;P<0.01). The number of CD8⁺S6F1⁺ (cytotoxic T) cells in HD patients was also less than that in healthy subjects (247±104 vs 122±83/µl; NS). During a 6-month period of rhEPO therapy, we found that the low level of CD4⁺CD45RA⁺ cells gradually increased (from 112±18 to 163±24/µl;P<0.01) with the elevation of hematocrit values (from 21.5±1.7 to 28.2±3.5%;P<0.05). The number of CD3⁺HLA-DR⁺ cells decreased after 1 month of rhEPO therapy (from 93±14 to 46±13/µl) and gradually declined throughout the 6-month study period. In ourin vitro study, we demonstrated that no effects were observed on [³H]thymidine uptake in the T cell subsets at various concentrations of rhEPO. These results suggest that rhEPO-induced immunoregulation is mediated by an indirect stimulatory effect on the immune system, this stimulation being accompanied by an improvement in physical condition.     

Plasma carnitine profile during chronic renal anemia treatment with recombinant human erythropoietin

Recombinant human erythropoietin (epoetin) is widely used for correction of anaemia in patients with chronic renal disease and its efficacy has been confirmed in numerous studies. Disturbances in carnitine metabolism may also contribute to the development of renal anaemia. Although increases in erythrocyte count (RBC) and changes in RBC metabolism during L-carnitine administration have been observed, supplementation with L-carnitine in anaemic hemodialysis patients is not routine. The aim of our study was to determine the influence of epoetin on hematological parameters and plasma carnitine profile in anaemic hemodialysis patients. 36 hemodialysis patients (22 men, 14 female, aged from 17 to 64 years, mean 43) and 30 healthy volunteers (12 men, 18 female, aged from 25 to 65 years, mean 40) were studied. Epoetin (Eprex, Janssen-Cilag) was administered subcutaneously for twelve months with the starting dose 2000 IU three times per week (range from 75 to 133, mean 102 +/- 21 IU/kg/week). The target hemoglobin (Hb) range at the time of the study was between 10-11 g/dL. Laboratory markers of hematological response, carnitine and iron status, were measured before epoetin administration and then controlled every three months. During epoetin treatment a significant increase in Hb concentration was observed (100% of patients responded to epoetin). In the third and six month of epoetin treatment, along with a significant increase in mean reticulocyte count and the highest increment of RBC count and Hb levels, probably due to increased erythropoiesis, a significant, transient decrease of mean total and free plasma carnitine levels was observed. This may suggest the utilisation of carnitine by a new RBC population. It also indicates that there is a need for L-carnitine in carnitine deficient maintenance hemodialysis patients particularily during erythropoiesis induced by epoetin treatment.     

Effect of recombinant human erythropoietin on the rate of Na+,H+-exchange in erythrocytes from patients with chronic renal failure on hemodialysis

The study explores the effect of recombinant human erythropoietin and the rate of Na⁺,H⁺-exchange in erythrocytes from patients with chronic renal failure undergoing hemodialysis. The rate of Na⁺,H⁺-exchange in erythrocytes from patients was higher than in the control and remained unchanged after 24 months of treatment with erythropoietin. Therapy with recombinant human erythropoietin does not normalize the Na⁺,H⁺-exchange mechanism. It is concluded that factors underlying disturbances of ion transport in erythrocytes from uremic patients cannot be corrected with erythropoietin. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 12, pp. 613–615, December, 1997     

Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial

We administered recombinant human erythropoietin to 25 anemic patients with end-stage renal disease who were undergoing hemodialysis. The recombinant human erythropoietin was given intravenously three times weekly after dialysis, and transfusion requirements, hematocrit, ferrokinetics, and reticulocyte responses were monitored. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. No organ dysfunction or other toxic effects were observed, and no antibodies to the recombinant hormone were formed. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease.     

Microcirculation and capillary permeability during hemodialysis in patients with renal insufficiency

Time course changes in microcirculation (MC) and capillary permeability (CP) were investigated in 191 patients with acute renal failure (ARF) and 45 patients with terminal chronic renal failure (CRF). Similar in type MC and CP disturbances were found in all CRF and oligoanuria ARF patients. These were more pronounced in CRF sufferers depending in degree on the disease severity. Knizeli's phenomenon ranged from 2.2.KII to 3.3.KIII. The total conjunctival index reached 22.99-25.20 in CRF and 19.4 in ARF. Unlike ARF patients, those with CRF had no positive trend in MC and CP. A transient change for the better came after hemodialysis and was seen in occasional patients. It is suggested that no response to hemodialysis is indicative of CRF and ARF poor prognosis. The trend in MC can help in prognostication of CRF development in acute cases.     

Effects of recombinant human erythropoietin on the plasma levels of vasoactive regulatory peptides in patients on maintenance hemodialysis

The plasma levels of nine vasoactive regulatory peptides were measured by radioimmunoassay in six stable patients with chronic renal failure on regular hemodialysis, before and during treatment with recombinant human erythropoietin (r-huEPO). All patients responded with significant increases in hemoglobin concentrations and hematocrit. Mean arterial blood pressure was not significantly changed nor were there any changes of body weight or interdialytic body weight gain. The mean plasma levels of atrial natriuretic peptide and motilin decreased significantly, by 38 and 16 percent respectively, during r-huEPO treatment. There were no changes in mean plasma levels of arginine vasopressin, calcitonin gene-related peptide, beta-lipotropin, gamma 2-melanocyte-stimulating hormone, neuropeptide Y, substance P or vasoactive intestinal peptide. No significant correlations were observed between changes of plasma peptide levels and changes of mean arterial blood pressure.