Richard L. DeGowin

Recombinant Human Erythropoietin Treatment in Pre-Dialysis Patients: A Double-Blind Placebo-Controlled Trial

STUDY OBJECTIVE To determine the efficacy and safety of recombinant human erythropoietin (r-HuEPO) in predialysis renal patients. DESIGN Randomized, double-blind, placebo-controlled trial for 8 weeks. SETTING Inpatient and outpatient facility in the Clinical Research Center of a university-based hospital. PATIENTS Fourteen adult subjects with renal insufficiency (mean serum creatinine, 473 mumol/L +/- 61 [6.2 +/- 0.8 mg/dL]) and anemia (mean hematocrit, 0.27 +/- 0.01). INTERVENTIONS Recombinant human erythropoietin, 50, 100, or 150 IU/kg body weight or placebo given intravenously three times per week. MEASUREMENTS AND MAIN RESULTS Subjects who received active r-HuEPO showed a dose-dependent rise in hematocrit; mean hematocrit increased 41% from 0.27 +/- 0.01 to 0.38 +/- 0.01. At the same time, erythrocyte mass rose 43% from 13.7 +/- 0.6 mL/kg in the baseline state to 19.6 +/- 1.0 mL/kg after treatment. Maximal oxygen consumption during exercise increased 9% from 16.0 mL/min.kg +/- 1.8 to 17.5 mL/min.kg +/- 1.9. CONCLUSIONS Recombinant human erythropoietin is effective and safe in ameliorating the anemia of pre-dialysis patients.

Erythropoiesis and Erythropoietin in Patients with Chronic Renal Failure Treated with Hemodialysis and Testosterone

Abstract Testosterone was administered to two patients with chronic renal failure (one patient was anephric) who were being treated with periodic hemodialysis. The hematocrit and plasma erythropoie...

The Safety and the Efficacy of Maintenance Therapy of Recombinant Human Erythropoietin in Patients With Renal Insufficiency

Ten anemic predialysis renal patients participated in a study to examine the long-term effects of recombinant human erythropoietin (r-HuEPO) treatment. The drug was initially given intravenously three times a week for 1 to 5 months, then by subcutaneous injections three times each week for 4 to 8 months, and finally by subcutaneous injection once weekly for 3 to 18 months. The duration of follow-up ranged from 11 to 29 months. Anemia was ameliorated in all participants. Mean hematocrit increased from a basal value of 26.8% to 35.1% during the intravenous phase and to 36.7% and 34.6% during the two subcutaneous periods. Mean weekly doses of erythropoietin (EPO) were 276 units/kg during intravenous therapy and 134 and 108 units/kg in the two subcutaneous periods. The differences in the doses were significant only between the intravenous and the two subcutaneous periods. Mean erythrocyte mass increased from a baseline value of 13.6 mL/kg to 20.4 mL/kg 8 months after initiation of treatment. Mean erythrocyte survival half-time was increased from 23 days before to 26 days, 8 months after r-HuEPO treatment, P less than 0.002. Mean blood pressure (mm Hg) was 105 before and 95 after treatment. Mean serum creatinine was 513 mumol/L (5.8 mg/dL) at the beginning of the study. At the time of this writing (11 to 29 months after treatment), seven patients have required dialysis treatment. There were three episodes of transient refractoriness to r-HuEPO documented during periods of infection and surgical procedures. All subjects tolerated the medication well, and no serious side effects attributable to the medication were noted. Furthermore, circulating antibodies against r-HuEPO were consistently negative.

Suppression of marrow stromal cells and microenvironmental damage following sequential radiation and cyclophosphamide

Abstract Persistent defects in marrow stroma may contribute to hemopoietic insufficiency in patients treated with combined modality therapy for malignancy. To assess the bone marrow failure following combined therapy, mice received intraperitoneal administration of four weekly doses of cyclophosphamide, 160 mg/kg (CY) one week after 1500 rad leg irradiation (LI). This treatment inhibited repopulation of endogenous nucleated cells to less than 60% of normal at one, two, four and six months post-irradiation. Leg irradiation alone suppressed the repopulation to about 75% of normal and cyclophosphamide alone suppressed to 80% of normal. Normal body weight and recovery of peripheral leukocytes and hematocrit to normal levels demonstrated the localized nature of the lesion. Differential marrow counts revealed that 1500 rad LI + CY suppressed erythroblasts, myeloid, and lymphoid cells more than either modality alone. To directly assess the damage of sequential 1500 rad LI + CY on the microenvironment, marrow stromal cells were flushed from the femoral marrow and cultured as adherent cell colonies. They were suppressed to less than 30% of normal for three months following combined modality treatment. Other progenitors, granulocyte-macrophage and spleen colony forming units (CFU-C and CFU-S respectively), were suppressed but exhibited different patterns of partial recovery. We conclude that multiple courses of cyclophosphamide starting one week after 1500 rad LI produced persistent damage to the microenvironment reflected by decreased marrow stromal cells and failure of hemopoietic cells and their progenitors to completely repopulate femoral marrow.

RETENTION OF RADIOIRON IN THE LUNGS OF A WOMAN WITH IDIOPATHIC PULMONARY HEMOSIDEROSIS.

Abstract This paper presents studies of a menopausal woman with idiopathic pulmonary hemosiderosis who had only slight hemoptysis, no measurable blood loss, but a major intrapulmonary hemorrhage. L...

Residual injury to the hemopoietic microenvironment following sequential radiation and busulfan

Our earlier studies in mice showed that sequential radiation and cyclophosphamide suppressed marrow stromal cells (MSC) and prevented local hemopoietic repopulation for several months. Because others have shown that busulfan administration caused marrow aplasia, we studied its ability, combined with radiation, to produce a persistent microenvironmental defect in mice. Intraperitoneal administration of four weekly doses of 20 mg/kg busulfan, starting one week after 1500 rad leg irradiation, produced a severe microenvironmental lesion for 6 months reflected by lack of repopulation in femoral marrow to greater than 50% of normal by MSC, hemopoietic stem cells (CFU-S), and granulocyte-macrophage precursors. Differential marrow cell counts revealed that precursors of hemopoietic cells were more profoundly affected than their progeny. Hemopoietic stem cells and MSC failed to recover in busulfan-treated mice at 6 months to the same extent as those treated with cyclophosphamide. In addition, the busulfan-treated mice had an excessive number of myeloid blast cells and a severe erythroid depletion suggesting that these animals were preleukemic. We conclude that: 1) sequential radiation and busulfan administration caused long-term microenvironmental damage reflected by incomplete repopulation of the femoral marrow and suppression of MSC, and 2) multiple courses of busulfan prevented hemopoietic repopulation longer than a similar regimen of cyclophosphamide.

Relationship of Early Proliferating Cells to Erythroblasts in Hemopoietic Colonies

Summary Labeled erythroblasts were found in the hemopoietic colonies of endocolonized mouse spleens 5 days postirradiation after 3HTdR had been administered 24—40 hr previously. No erythroblasts could be found in the spleens of other mice at the time of the administration of 3HTdR. About one third of the nonerythroblastic cells, which resembled medium to large leptochromatic lymphocytes, were labeled on day 4. One explanation for the findings is that some replicating cells resembling lymphocytes on day 4, transformed to erythroblasts by day 5.

Ultrastructural features of the early proliferating cells involved in hemopoietic colony formation.

After flash labeling with tritiated thymidine for autoradiography, a cohort of early proliferating autologous hemopoietic cells was examined in endocolonized mouse spleens with light and electron microscopy. During the first three to five days postirradiation, proliferating cells within colonies resembled medium to large immature lymphocytes. A thin rim of nuclear chromatin on an irregular inner nuclear membrane characterized the early cells. After day 5, erythroblasts were readily detected. Although unirradiated spleens contained myeloid and erythroid precursors, cells resembling lymphocytes were most frequently seen. Spleens of mice, receiving lethal total-body irradiation four days previously, contained very few cells synthesizing DNA and no erythroblasts. Macrophages ingesting nuclear material could be seen with light and electron microscopy.

Studies on the Activity of Pyruvate Kinase in Hemolysates of Normal and Glucose-6-Phosphate Dehydrogenase-deficient Erythrocytes.

Excerpt Pyruvate kinase catalyzes a key, adenosine triphosphate-generating step of anaerobic glycolysis. This pathway constitutes the main source of energy in mature erythrocytes of human beings. W...