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OBJECTIVE - To determine if chronic sympathetic deprivation is associated with anemia and a low erythropoietin response.
DESIGN - Survey of the prevalence and characteristics of anemia in patients with severe primary autonomic failure.
SETTING - A referral service for autonomic failure in a tertiary teaching hospital.
PATIENTS - 84 patients with primary autonomic failure who had symptomatic orthostatic hypotension.
INTERVENTION - Open-label trial with human recombinant erythropoietin.
RESULTS - Anemia was present in 32 of 84 patients (38%; 95% Cl, 27% to 50%). Plasma norepinephrine levels, measured in patients standing upright, were lower in the patient group with lower hemoglobin levels. Mean values in 22 patients with a hemoglobin level of less than 120 g/L were as follows: hemoglobin, 108 g/L (range, 87 to 118 g/L); hematocrit, 0.33; corrected reticulocyte counts, 0.008; mean corpuscular volume, 89 fL (89 microns 3); serum iron, 16.5 mumol/L (92 micrograms/dL); total iron binding capacity, 43.3 mumol/L (242 micrograms/dL); ferritin, 184 micrograms/L; serum vitamin B12, 410 pmol/L (556 pg/mL); and serum folate, 22.7 nmol/L (10 ng/mL). No relation was found between serum erythropoietin and blood hemoglobin levels. In seven of nine patients with autonomic failure who had hemoglobin levels less than 120 g/L, serum erythropoietin levels decreased below the 95% confidence interval corresponding to patients with iron deficiency anemia. Therapy with recombinant erythropoietin improved mean hemoglobin levels (from 108 to 133 g/L) in all patients treated (n = 5) at relatively low doses (25 to 50 units/kg body weight, subcutaneously, three times a week).
CONCLUSIONS - Our data support the hypothesis that the sympathetic nervous system stimulates erythropoiesis in humans because anemia is a frequent occurrence in patients with severe autonomic failure and is associated with a blunted erythropoietin response.
Iron supplementation is required by most dialysis patients receiving recombinant human erythropoietin. The efficacy of oral iron is variable in these patients, and many require the use of intravenous iron dextran to maintain adequate iron levels, defined as transferrin saturation greater than 20%, serum ferritin greater than 100 ng/mL, and serum iron greater than 80 micrograms/dL. To determine the efficacy of different oral iron preparations in maintenance of iron status, we prospectively studied 46 recombinant human erythropoietin-treated patients and randomized them to receive different oral iron preparations. These four preparations included Chromagen (ferrous fumarate; Savage Laboratories, Melville, NY), Feosol (ferrous sulfate; SmithKline Beecham, Inc, Pittsburgh, PA), Niferex (polysaccharide; Central Pharmaceuticals, Inc, Seymour, IN), or Tabron (ferrous fumarate; Parke-Davis, Morris Plains, NJ). All patients were prescribed approximately 200 mg of elemental iron daily of their assigned iron preparation with at least 100 mg ascorbic acid daily for 6 months. At baseline and bimonthly during the study, serum iron, transferrin saturation, ferritin, hematocrit, and recombinant human erythropoietin dose were monitored; in addition, compliance and side effects were recorded by patient interview. All patients were able to maintain target hematocrit during the 6 months of study. However, there were differences in the trends of serum iron, percent transferrin saturation, and ferritin when considered singly or in combination between the four groups of iron medications. The percent of laboratory values measured over the study period in each group that met the criteria of transferrin saturation more than 20% was greatest in the Tabron group (58%), followed by the Feosol (47%), Chromagen (33%), and Niferex (31%) groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Activation of the TAL1 (or SCL) gene, originally identified through its involvement by a recurrent chromosomal translocation, is the most frequent molecular lesion recognized in T-cell acute lymphoblastic leukemia. The protein products of this gene contain the basic-helix-loop-helix motif characteristic of a large family of transcription factors that bind to the canonical DNA sequence CANNTG as protein heterodimers. TAL1 expression by erythroid cells in vivo and in chemical-induced erythroleukemia cell lines in vivo suggested the gene might regulate aspects of erythroid differentiation. Since the terminal events of erythropoiesis are controlled by the glycoprotein hormone erythropoietin (Epo), we investigated whether the expression or activity of the TAL1 gene and its protein products were affected by Epo in splenic erythroblasts from mice infected with an anemia-inducing strain of Friend virus (FVA cells). Epo elicited a rapid, dose-related increase in TAL1 mRNA by increasing transcription of the gene and stabilizing one of its mRNAs. An Epo-inducible TAL1 DNA binding activity was identified in FVA cell nuclear extracts that subsequently decayed despite accumulating mRNA and protein. Induction of DNA binding activity was associated temporally with Epo-induced phosphorylation of nuclear TAL1 protein. These results indicate that Epo acts at both transcriptional and posttranscriptional levels on the TAL1 locus in Friend virus-induced erythroblasts and establish a link between Epo signaling mechanisms and a member of a family of transcription factors involved in the differentiation of diverse cell lineages.
Five long-term hemodialysis patients with clinical iron overload were treated with 300 U/kg of recombinant human erythropoietin (rHuEPO) intravenously (IV) after each hemodialysis. The patients were phlebotomized after each hemodialysis at any time the predialysis hematocrit was 35% or greater. Over a period of 1 year, the average phlebotomy rate varied from 0.5 to 1.1 U/wk with a mean phlebotomy rate of 45.8 +/- 5.6 U/yr (range, 27 to 57 U). The mean serum ferritin decreased from 8,412 +/- 1,599 micrograms/L (ng/mL) to 3,007 +/- 1,129 micrograms/L (ng/mL), and the mean iron removal over this period was 9.5 g. Liver iron deposition, as measured by density on computed tomographic (CT) scan, improved, while skin color lightened significantly. Patients tolerated phlebotomy with no major symptoms or complications and exhibited no change in the hemogram or serum chemistries. In patients with severe iron overload, changes in serum ferritin with erythropoietin treatment alone may not reflect true change in iron burden. Use of high-dose erythropoietin and phlebotomy is an effective and safe (at least for 1 year) method of reducing iron overload in long-term hemodialysis patients.
Recombinant human erythropoietin is effective therapy for the anemia of chronic renal failure. Hypertension, seizures, dialysis access thromboses, and clotted dialyzers have been reported as problems associated with the use of this drug. To test the hypothesis that low-dose erythropoietin is effective and safe, we gave 37 chronic hemodialysis patients this compound (3,000 units, i.v.) three times each week for 3 months. Before and for 3 months during therapy, we measured hemoglobin, hematocrit, blood transfusions, blood pressure, access thromboses, seizures, and clotted dialyzers. After 2 months of treatment, mean hemoglobin concentration and mean hematocrit increased significantly. Five patients had no increase in either value. In 4 of these 5 nonresponders, blood loss accounted for treatment failure. Neither blood pressure nor the incidence of access thromboses, seizures, and clotted dialyzers changed during the 3 months of therapy. We conclude that recombinant human erythropoietin is effective as treatment for the anemia of chronic renal failure at much lower doses than have been reported previously. The low incidence of adverse events may be related to the low dose used.
To test the hypothesis that low-dose recombinant human erythropoietin (r-HuEpo) would be effective and safe therapy for the anemia of end-stage renal failure, we studied 37 chronic hemodialysis patients for 3 months before and 6 months after beginning treatment with r-HuEpo, 3,000 U, administered initially intravenously (IV) three times weekly. Hematocrit increased from a mean of 25.2 vol% into the target range (mean, 32.2 vol%, a 28% increase) by 4 months. Transfusion requirements were dramatically reduced. Eight patients (22%) had exacerbated or new development of hypertension, while in trials using higher doses this occurred in 35%. Vascular access thrombosis, dialyzer clotting, and seizures were not seen more frequently during r-HuEpo therapy. Dialyzer reuse was not affected. Low-dose r-HuEpo therapy is effective in most hemodialysis patients and may be associated with less adverse effects because of the slower increase in blood viscosity. As targets are reached, downward dosage adjustments need to be smaller when using an initial low-dose regimen.
The hematologic response of 65 continuous ambulatory peritoneal dialysis (CAPD) patients to subcutaneous recombinant human erythropoietin (rHuEPO) was compared with that of 369 hemodialysis patients (HD). Pretherapy transfusions were more common in HD than CAPD. The response was measured as the change in hematocrit after 70 or more days of therapy (or as the hematocrit change normalized by a weekly dose) in CAPD patients. The weekly rHuEPO dose did not differ, but the dosing frequency was less in CAPD than in HD patients. Hematologic response parameters were greater in CAPD. Multivariate analysis showed that the response in both groups varied inversely with the frequency of dosing and with pretherapy baseline hematocrit. In HD subjects, the response also varied inversely with previous transfusion history. The authors concluded that CAPD patients responded better to rHuEPO than HD patients. This may be a result, in part, of lower ongoing blood losses. Patients with more severe anemias responded less well, whereas more sensitive patients were dosed less frequently.
OBJECTIVE - To determine if the simultaneous initiation of continuous ambulatory peritoneal dialysis (CAPD) and Erythropoietin therapy masks the hematocrit (Hct) rise that frequently follows the initiation of CAPD alone.
DESIGN - Single-center retrospective analysis.
SETTING - University multidisciplinary dialysis program.
PATIENTS - All adult CAPD patients with a Hct less than or equal to 28% whose nephrologist felt they would benefit from Erythropoietin therapy and who did not have technical reasons for exclusion (N = 25).
INTERVENTIONS - Eight patients began CAPD and Erythropoietin alfa subcutaneously, at a dose of 128 +/- 9 (X +/- SEM) units/kg/week at the same time. Seventeen patients already on CAPD for 8.7 +/- 1.5 months received Erythropoietin alfa subcutaneously at a dose of 124 +/- 7 units/kg/week. Pre-epoetin Hct's were similar.
MAIN OUTCOME MEASURES - Hematocrit changes, status of iron stores, incidence of peritonitis, and dosage of Erythropoietin.
RESULTS - In 1 month, the group initiating both therapies simultaneously demonstrated a mean Hct rise of 7.6 +/- 0.5% while established CAPD patients receiving Erythropoietin increased their Hct by only 4.7 +/- 1.0% (p less than .03). Iron status could not explain this difference. Peritonitis did not appear to dampen the Hct rise following Erythropoietin in either CAPD group. By 2 months after Erythropoietin, the differences were less apparent.
CONCLUSION - The early rapid increase in Hct is probably the combined effect of CAPD and Erythropoietin and should not be attributed to Erythropoietin alone. When comparing responses to Erythropoietin from patients on different therapies, the timing of dialysis initiation and Erythropoietin initiation must be considered.