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PubMed1996

Optimal timing of repeated rh-erythropoietin administration improves its effectiveness in stimulating erythropoiesis in healthy volunteers.

We studied the effect of recombinant human erythropoietin (rhEPO) on erythropoiesis when given at different time intervals to healthy adults. 15 volunteers were randomly selected to receive rhEPO (2 x 300 U/kg) and parenteral iron (2 x 200mg) either within a 24 h or 72 h interval. Controls received parenteral iron only. Maximum EPO levels were found 24 h after the first intravenous injection (day 1) with a mean value of 364 and 390 U/l for the rhEPO-treated groups. When second rhEPO administration was after 72 h (group III), volunteers showed significantly higher absolute reticulocyte counts and a higher percentage of young RNA-rich reticulocytes (HFR ratio) over several days compared to those who received rhEPO within a 24 h interval (group II). Both rhEPO-treated groups showed an increase in the mean reticulocyte cell volume. Reticulocyte haemoglobin concentration was inversely correlated with the increasing cell size with a nadir on day 8. Reticulocyte haemoglobin content showed a significant decrease in group II after day 5. Serum ferritin levels showed an inverse pattern to the rate of erythropoiesis. After an initial rise, the serum ferritin decrease was most pronounced in group III. Contrary to previous reports with oral iron supplementation, functional iron deficiency was not seen during rhEPO stimulation, due to parenteral iron administration. Our data suggest that the time has interval between repeated administrations of rhEPO has an important influence on its pharmacodynamics. rhEPO given within an interval of 72 h was more effective in stimulating erythropoiesis than administration within 24 h interval for the same total dose.

Adult↗
PubMed1990

Accelerated erythropoiesis: the hidden benefit of autologous donation.

The risks associated with the administration of blood products have increased efforts to avoid homologous transfusions. Preoperative autologous donation has received renewed interest as a method of decreasing homologous transfusion requirements. Autologous donations may also stimulate postoperative erythropoiesis. The purpose of this study is to evaluate the effect of an aggressive autologous donation program on postoperative erythropoiesis. Ten adult male baboons were divided into two groups. The autologous group (n = 5) donated an average of 2 units of blood per week for 5 weeks before operation. The control group (n = 5) had no preoperative treatment. All animals then underwent a laparotomy and exchange transfusion with hetastarch to a final hematocrit of 15 percent. The time required to recover to hematocrits of 20 percent (3.3 vs. 5.7 days, p less than 0.01), 25 percent (7.0 vs. 8.8 days, p less than 0.05), and 30 percent (11.1 vs. 17.7 days, p less than 0.01) was shorter in the autologous group. The autologous group had more intense reticulocytosis during the first 4 postoperative days (p less than 0.03). The data show that participation in an aggressive autologous donation program improves the erythropoietic response to anemia in the postoperative setting. This represents a hidden benefit of preoperative autologous donations and suggests that more aggressive donation schedules may be clinically beneficial. Recognition of that acceleration of erythropoiesis by autologous donation could further reduce the need for transfusion of homologous blood.

Animals↗
PubMed2004

The minimal promoter plays a major role in silencing of the galago gamma-globin gene in adult erythropoiesis.

The human gamma-globin gene and its orthologous galago gamma-globin gene evolved from an ancestral epsilon-globin gene. In galago, expression of the gamma-gene remained restricted to the embryonic stage of development, whereas in humans, expression of the gamma-gene was recruited to the fetal stage. To localize the cis-elements responsible for this developmentally distinct regulation, we studied the expression patterns of the human gamma-gene driven by either the human or the galago gamma-promoters in transgenic mice. gamma-gene transcription driven by either promoter reached similar levels in embryonic erythropoiesis. In adult erythropoiesis the gamma-gene was silenced when controlled by the galago gamma-promoter, but it was expressed at a high level when it was linked to the human gamma-promoter. By a series of gamma-promoter truncations the sequences required for the down-regulation of the galago gamma-globin gene were localized to the minimal promoter. Furthermore, by interchanging the TATA, CCAAT, and CACCC elements between the human and galago minimal promoters we found that whereas each box made a developmentally distinctive contribution to gamma-globin gene expression, the CACCC box was largely responsible for the down-regulation of the gamma-gene in adult erythropoiesis.

Animals↗
PubMed2006

Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development.

Hypoxia-inducible factor-1 (HIF-1) regulates the transcription of genes whose products play critical roles in energy metabolism, erythropoiesis, angiogenesis, and cell survival. Limited information is available concerning its function in mammalian hematopoiesis. Previous studies have demonstrated that homozygosity for a targeted null mutation in the Hif1alpha gene, which encodes the hypoxia-responsive alpha subunit of HIF-1, causes cardiac, vascular, and neural malformations resulting in lethality by embryonic day 10.5 (E10.5). This study revealed reduced myeloid multilineage and committed erythroid progenitors in HIF-1alpha-deficient embryos, as well as decreased hemoglobin content in erythroid colonies from HIF-1alpha-deficient yolk sacs at E9.5. Dysregulation of erythropoietin (Epo) signaling was evident from a significant decrease in mRNA levels of Epo receptor (EpoR) in Hif1alpha-/- yolk sac as well as Epo and EpoR mRNA in Hif1alpha-/- embryos. The erythropoietic defects in HIF-1alpha-deficient erythroid colonies could not be corrected by cytokines, such as vascular endothelial growth factor and Epo, but were ameliorated by Fe-SIH, a compound delivering iron into cells independently of iron transport proteins. Consistent with profound defects in iron homeostasis, Hif1alpha-/- yolk sac and/or embryos demonstrated aberrant mRNA levels of hepcidin, Fpn1, Irp1, and frascati. We conclude that dysregulated expression of genes encoding Epo, EpoR, and iron regulatory proteins contributes to defective erythropoiesis in Hif1alpha-/- yolk sacs. These results identify a novel role for HIF-1 in the regulation of iron homeostasis and reveal unexpected regulatory differences in Epo/EpoR signaling in yolk sac and embryonic erythropoiesis.

Animals↗
PubMed2004

Hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors in diagnosing iron-deficient erythropoiesis.

BACKGROUND: The purpose of this study was to test the hypothesis that hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors are sensitive variables in detecting iron-deficient erythropoiesis in healthy subjects and hemodialysis patients. METHODS: Study 1: Twenty-one blood donors donated 450 mL blood. During the following 2 weeks blood samples were analyzed for the variables mentioned above. Study 2: Twenty-eight blood donors received 10,000 U recombinant human erythropoietin (rHuEPO) twice in the first week or placebo, after they had donated 450 mL blood. During the following 3 weeks the blood samples were analyzed for the variables mentioned in Study 1. Study 3: Eighteen hemodialysis patients receiving rHuEPO and iron treatment had either iron treatment discontinued for 4 weeks, after which iron was resumed, or received unchanged treatment. During 8 weeks blood samples were analyzed for the variables mentioned in Study 1. RESULTS: Study 1: Blood donation induced an increase in hypochromic reticulocytes of 178%, in hypochromic erythrocytes the increase was 267%, and in p-transferrin receptors 32%. Study 2: Treatment with rHuEPO induced a more pronounced increase than placebo in hypochromic reticulocytes (232% vs. 158%) and hypochromic erythrocytes (1240% vs. 300%), but not in p-transferrin receptors. Study 3: Discontinuation of iron treatment did not cause any significant differences in the variables mentioned above between the two groups, but caused a 25% decrease in p-ferritin. When iron treatment was resumed, p-ferritin increased by 19%. We found no significant changes in the control group. CONCLUSIONS: Hypochromic reticulocytes, hypochromic erythrocytes and p-transferrin receptors are sensitive variables in the early detection of iron-deficient erythropoiesis in healthy subjects, but in this study the iron withdrawal period was too short to show the value of these variables in the detection of iron-deficient erythropoiesis in hemodialysis patients.

Adolescent↗
PubMed2001

The synergistic effect of thrombopoietin in erythropoiesis with erythropoietin and/or IL-3 and myelopoiesis with G-CSF or IL-3 from umbilical cord blood cells of full-term neonates.

The authors sought to determine whether recombinant human thrombopoietin (TPO) acts synergistically with other cytokines on burst-forming unit-erythroid (BFU-E)-derived and colony-forming unit-granulocyte/macrophage (CFU-GM)-derived colony formations from cord blood. Cord blood nonadherent mononuclear cells (MNC) from normal full-term neonates were cultured in a methylcellulose system. When cultured with 5 x 10(4) MNC/mL, erythropoietin (EPO) 2 U/mL, interleukin-3 (IL-3) 50 ng/mL, and/or TPO 400 ng/mL (experiment 1), the addition of TPO to EPO gave rise to more BFU-E-derived colonies (p = .002). The addition of TPO to EPO + IL-3 gave rise to more BFU-E-derived colonies (p = .006) also. TPO synergizes erythropoiesis from cord blood. When cultured with IL-3 50 ng/mL, granulocyte colony-stimulating factor (G-CSF) 25 ng/mL, and/or TPO 400 ng/mL, the addition of TPO to IL-3 gave rise to more CFU-GM-derived colonies (p = .002). The addition of TPO to G-CSF gave rise to more CFU-GM-derived colonies (p = .002) also. TPO synergizes myelopoiesis from cord blood. Thus, TPO has synergistic effects on both erythropoiesis and myelopoiesis from cord blood. In the identical conditions of culture, cord blood had significantly greater BFU-E-derived or CFU-GM-derived colony formation than bone marrow (in a previous report by the authors) did. When cultured under conditions similar to those of experiment 1, but with 1 x 10(4) cord blood MNC/mL and TPO 100 ng/mL (experiment 2), results similar to those in the experiment 1 also revealed that TPO has synergistic effects on erythropoiesis and myelopoiesis from cord blood. In every individual assay, the numbers of BFU-E-derived or CFU-GM-derived colonies in experiment 1 were significantly higher than those in experiment 2.

Cell Count↗
PubMed2006

Insulin-like growth factor-I stimulates erythropoiesis when administered enterally.

BACKGROUND: Insulin-like growth factors I and II (IGF-I and IGF-II) are potent growth factors involved in development. IGF-I stimulates proliferation of erythropoietic progenitors and parenteral IGF-I administration stimulates in vivo erythropoiesis in animals. IGF-I and IGF-II are both present in mammalian milks and when milk-borne, are resistant to neonatal gastrointestinal degradation. Whether milk-borne IGF-I or IGF-II regulates neonatal erythropoiesis in not known. We hypothesized that physiological doses of enteral IGFs stimulate erythropoiesis in suckling rats. METHODS: Eight day-old Sprague Dawley rats were artificially fed for 4 days with rat milk substitute (RMS) or RMS supplemented with physiological levels of IGF-I or IGF-II. Rats fed IGF-I and IGF-II were compared to control RMS. Blood and marrow were collected; measures of red cell mass, measures of erythropoietic stimulus, and indices of iron status were measured. RESULTS: Rats fed IGF-I had higher hemoglobin (Hb) levels (100 +/- 10 g/l), compared to those fed RMS (94 +/- 9) or IGF-II (91 +/- 6), p < 0.001. After IGF-I supplementation, red blood cell counts (RBC) (p < 0.04) and hematocrits (p < 0.002) were also higher. Plasma erythropoietin (Epo) levels, reticulocytes, plasma iron and erythrocyte iron incorporation were similar. CONCLUSION: Intact enteral IGF-I reaches distal erythropoietic tissue resulting in greater red cell mass, but not by increasing plasma Epo levels or by altering cellular iron transport.

Animals↗
PubMed1968

Enhanced erythropoiesis with concomitant diminished granulopoiesis in preirradiated recipient mice. Evidence for a common stem cell.

Three different methods of measuring the proliferative capacity of transplanted mouse bone marrow were used to study the effects of preirradiation of the recipient. Recipient mice were exposed to 700 R and given graded numbers of syngeneic bone marrow. 7 days were allowed for proliferation of these cells, and then the granulocytic or erythrocytic progeny was measured. The former was determined by the response to endotoxin, and the latter by the incorporation of radioactive iron into newly formed red blood cells. Erythropoiesis, therefore, could be measured independently from granulopoiesis by these techniques. The third method used was the spleen colony method of Till and McCulloch (5). Recipient animals exposed to 150 R preirradiation, 7 days before 700 R and bone marrow transplantation, demonstrated an increase in erythropoiesis with a concommittant decrease in granulopoiesis compared to similar recipients not preirradiated. The spleen colony technique showed that while the number of colonies were the same in both groups, the colonies themselves were significantly larger in the preirradiated animals. Since such colonies are primarily erythropoietic, this finding is consistent with the other methods. The results can be explained by assuming the presence of a hematopoietic stem cell which, in these preirradiated recipients, is directed towards erythropoiesis at the expense of granulopoiesis.

Animals↗
PubMed1981

Expression of resistance to Friend virus-stimulated erythropoiesis in bone marrow chimeras containing Fv-2rr and Fv-2ss bone marrow.

Bone marrow chimeras were formed containing mixtures of DBA/2 (Fv-2ss, Hbbdd) and B10.D2 (Fv-2rr, Hbbss) bone marrow. When these mice were infected with the polycythemia-inducing strain of Friend virus, erythropoiesis was stimulated, but the proportion of B10.D2 hemoglobin fell rapidly and newly synthesized hemoglobin was essentially all of the DBA/2 type. The treatment of infected polycythemic chimeras with phenylhydrazine lowered the hematocrit and restored the synthesis of B10.D2 hemoglobin. These results imply that B10.D2 erythroid precursors are intrinsically resistant to Friend virus-stimulated erythropoiesis. The experiments also suggest that virus-stimulated erythropoiesis is not mediated by a factor or cell-cell interactions, unless such factors or interactions do not act across strain barriers.

Alleles↗
PubMed2000

Erythropoietin receptors that signal through Stat5 or Stat3 support fetal liver and adult erythropoiesis: lack of specificity of stat signals during red blood cell development.

Erythropoietin (Epo) is essential for formation of mature red blood cells (RBC). However, the function of Epo receptor (EpoR)-dependent signaling pathways in the regulation of erythropoiesis remains unclear. To determine whether specific Stat signals are required for RBC development, we changed the Stat signaling specificity of the EpoR. The wild-type EpoR activates only Stat5. Thus, we substituted the major Stat5 binding sites (residues 343 and 401) in the EpoR cytoplasmic region with the Stat3 binding/activation motif from gp130. We demonstrated that activated EpoRs containing a single substitution stimulate Stat5 and Stat3, whereas an EpoR with both substitutions stimulates Stat3 but not Stat5. We then determined the ability of these receptors to support fetal liver and adult erythropoiesis. Our results show that erythropoiesis is stimulated by EpoRs that activate Stat5, both Stat5 and Stat3, or Stat3 in place of Stat5. These findings demonstrate that the specificity of EpoR Stat signaling is not essential for RBC development.

Animals↗
PubMed2004

Adrenergic modulation of erythropoiesis following severe injury is mediated through bone marrow stroma.

BACKGROUND: Severe trauma leads to hematopoietic failure and bone marrow (BM) dysfunction that manifests clinically as a persistent anemia and leukopenia. The impact of severe trauma and its associated hyperadrenergic state on erythropoiesis has not been described. The aim of this study was to demonstrate the effects of adrenergic agonists and antagonists on erythropoiesis, both in normal bone marrow mononuclear cells (BMNC) and stroma-depleted BM. METHODS: Urine epinephrine (EPI) and norepinephrine (NE) excretion from severely injured patients was assessed via enzyme-linked immunoadsorbent assay (ELISA). Erythropoiesis was assessed by the growth of erythroid progenitors-erythroid burst forming units and colony forming units (BFU-E and CFU-E)-in normal human BM in the presence of adrenergic agonists and antagonists at varying concentrations. Parallel cultures, depleted of BM stroma by passage through nylon wool columns, were compared. RESULTS: Urine NE excretion was elevated in all samples from days 1 to 10 following injury (average 139 +/- 59 mcg/day vs. control 35 +/- 9 mcg/day). In vitro doses of NE, EPI, and isoproterenol (ISO) exerted a stimulatory effect on BFU-E colony growth in BMNCs (expressed as percentage of control: 324 +/- 30, 272 +/- 16, 212 +/- 95, vs. 100%), but had no effect on stroma-depleted BM. CONCLUSIONS: There is a substantial and persistent hyperadrenergic state seen after severe injury that may last for up to a week. Adrenergic agonists have a clear stimulatory effect on the growth of primitive erythroid precursors in normal BM. The adrenergic stimulus appears to be mediated via BM stroma.

Adrenergic Agents↗
PubMed2001

In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis.

GATA-1 is a transcription factor essential for erythroid/megakaryocytic cell differentiation. To investigate the contribution of individual domains of GATA-1 to its activity, transgenic mice expressing either an N-terminus, or an N- or C-terminal zinc finger deletion of GATA-1 (Delta NT, Delta NF or Delta CF, respectively) were generated and crossed to GATA-1 germline mutant (GATA-1.05) mice. Since the GATA-1 gene is located on the X-chromosome, male GATA-1 mutants die by embryonic day 12.5. Both Delta NF and Delta CF transgenes failed to rescue the GATA-1.05/Y pups. However, transgenic mice expressing Delta NT, but not the Delta NF protein, were able to rescue definitive hematopoiesis. In embryos, while neither the Delta CF protein nor a mutant missing both N-terminal domains (Delta NTNF) was able to support primitive erythropoiesis, the two independent Delta NT and Delta NF mutants could support primitive erythropoiesis. Thus, lineage-specific transgenic rescue of the GATA-1 mutant mouse revealed novel properties that are conferred by specific domains of GATA-1 during primitive and definitive erythropoiesis, and demonstrate that the NT and NF moieties lend complementary, but distinguishable properties to the function of GATA-1.

Animals↗
PubMed2005

Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure.

AIMS: Anaemia is often observed in patients with chronic heart failure (CHF), and it may be associated with a worse prognosis. Aim of this study was to identify the individual mechanisms of anaemia in CHF patients. METHODS AND RESULTS: One hundred and forty-eight consecutive patients with haemoglobin concentration <13 g/dL (if males) or <12 g/dL (if females) were enrolled. Factors responsible for anaemia were investigated by evaluating endogenous erythropoietin (Epo) production, serum cytokines levels, body iron status, and iron supply for erythropoiesis. Most patients (57%) presented anaemia of chronic disease and among them, 92% showed evidence of a defective endogenous Epo production. This was indicated by an observed/predicted log(serum Epo) ratio less than 0.8 and/or a defective iron supply for erythropoiesis diagnosed by low transferrin saturation and/or increased value of soluble transferrin receptor. According to regression analysis sex, renal failure, and serum Epo were correlated with anaemia. CONCLUSION: According to our study, about half of anaemic CHF patients showed anaemia of chronic disease with blunted endogenous Epo production and/or a defective iron supply for erythropoiesis. Determination of the individual mechanisms of anaemia in CHF could justify a rational therapeutic approach to anaemia.

Anemia↗
PubMed1992

Protein deficiency impairs erythropoiesis in rats by reducing serum erythropoietin concentration and the population size of erythroid precursor cells.

Erythropoietin (EPO), a glycoprotein produced mainly by the kidney, is the major physiological regulator of erythropoiesis. We developed a sensitive and rapid ELISA for measurement of rat serum EPO with two monoclonal antibodies that recognize different epitopes. To understand the mechanism by which erythropoiesis is impaired in rats deficient in dietary protein, we investigated the levels of the immunoreactive EPO (iEPO) in serums and erythroid precursor cells in hemopoietic tissues during protein deprivation. The iEPO level of 32-d-old rats fed a protein-free diet was lowered to one-third that of rats fed 20% casein at 6 h after protein deprivation began. Protein deprivation decreased the number of EPO-responsive cells in spleen. These results indicate that the impairment of erythropoiesis during protein deficiency is caused by the decrease in serum EPO and the subsequent reduction of the population size of erythroid precursor cells in spleen.

Animals↗
PubMed1987

Changes in minor transcripts from the alpha 1 and beta maj globin and glutathione peroxidase genes during erythropoiesis.

We have analysed the transcriptional regulation of the murine alpha 1 and beta maj globin genes and the glutathione peroxidase (GSHPx) gene, which are all highly expressed during erythropoiesis. The levels of minor RNAs compared to the major message were monitored throughout differentiation within the erythroid lineage. For each gene, upstream transcripts arise from distinct clusters of sites which are regulated differently during differentiation: some occur only during early erythropoiesis, some occur early and persist to the terminal stages, while others accumulate later and roughly in parallel with the main RNA transcript. In addition, opposite strand transcripts from the GSHPx gene were found in increasing amounts during later stages of erythropoiesis. The initiation sites for specific subsets of these minor transcripts lie close to sequences known to be involved in globin gene regulation (i.e. the TATA, CAAT and the CACCCT boxes) or other conserved sequences; others lie close to developmentally regulated DNase I hypersensitive sites around the globin and GSHPx genes.

Animals↗
PubMed1998

Uterine environment and breed effects on erythropoiesis and liver protein secretion in late embryonic and early fetal swine.

In this study we investigated erythropoiesis and fetal liver protein secretion during late embryonic (Day 24 and Day 30) and early fetal (Day 40) development in pigs from domestic white crossbred (WC) gilts with a normal (intact; INT) or crowded (unilateral hysterectomized/ovariectomized; UHO) uterine environment, or from prolific Chinese Meishan (MS) gilts. Increased fetal weight, fetal liver weight, placental weight, total red blood cells, hematocrit, blood hemoglobin content, and maternal plasma erythropoietin (EPO) levels were observed as gestation advanced. Cultured fetal liver secretion of transferrin and a protein of Mr 12500 and pI 7.5 also increased as gestation advanced. Fetal plasma EPO declined between Day 30 and Day 40. Differential counts of circulating erythroid precursors revealed a decline in basophilic erythroblasts and polychromatic erythroblasts between Day 24 and Day 40, an increase in orthochromatic erythroblasts on Day 30 followed by a drop on Day 40, and an increase in the percentage of reticulocytes/ erythrocytes from < 1.0% to approximately 90% of circulating red blood cells between Day 24 and Day 40. Differences among the treatment groups included a lower fetal survival percentage in UHO (vs. INT or MS) on Day 40, and higher maternal hematocrits, fetal weights, fetal hematocrits, fetal EPO levels, and liver transferrin secretion in WC vs. MS pigs. MS pigs had a lower percentage of polychromatic erythroblasts overall and a higher percentage of orthochromatic erythroblasts on Day 24 followed by a higher percentage of erythrocytes on Day 40 than WC pigs, suggesting a more mature erythron (circulating red blood cells plus erythropoietic tissue) in the MS pigs. Covariate analysis indicated that MS had larger placentae per unit of body weight than did WC. Conclusions were that 1) Days 24-40 of gestation is a critical time for fetal erythropoiesis in pigs as well as survival in a crowded uterine environment, 2) the MS breed may differ in the development of the fetal erythropoietic system because of altered fetal or uterine physiology, and 3) the UHO procedure did not significantly affect erythropoiesis in the fetuses studied but did alter fetal survival and the relationship between fetal weight and both hematocrit and hemoglobin on Day 40.

Animals↗
PubMed2005

Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor.

Although clinical and experimental studies have long suggested a role for the renin-angiotensin system (RAS) in the regulation of erythropoiesis, the molecular basis of this role has not been well understood. We report here that transgenic mice carrying both the human renin and human angiotensinogen genes displayed persistent erythrocytosis as well as hypertension. To identify the receptor molecule responsible for this phenotype, we introduced both transgenes into the AT1a receptor null background and found that the hematocrit level in the compound mice was restored to the normal level. Angiotensin II has been shown to influence erythropoiesis by two means, up-regulation of erythropoietin levels and direct stimulation of erythroid progenitor cells. Thus, we conducted bone marrow transplantation experiments and clarified that AT1a receptors on bone marrow-derived cells were dispensable for RAS-dependent erythrocytosis. Plasma erythropoietin levels and kidney erythropoietin mRNA expression in the double transgenic mice were significantly increased compared with those of the wild-type control, while the elevated plasma erythropoietin levels were significantly attenuated in the compound mice. These results provide clear genetic evidence that activated RAS enhances erythropoiesis through the AT1a receptor of kidney cells and that this effect is mediated by the elevation of plasma erythropoietin levels in vivo.

Angiotensin II↗
PubMed1985

Effect of cyclosporine and delayed graft function on posttransplantation erythropoiesis.

The effect of delayed graft function and immunosuppressive drugs on posttransplant erythropoiesis was studied prospectively in 18 living-related (LR) and 84 cadaver-donor (CD) recipients. Eight of 18 LR and 20 of 84 CD recipients received antilymphoblast globulin (ALG) in addition to azathioprine and prednisone. Sixty-four CD recipients received cyclosporine (CsA) with prednisone. In the absence of rejection reticulocytosis began 6.7 +/- 0.2 days following graft implantation in azathioprine-only-treated LR recipients. This was lengthened by ALG to 9.4 +/- 0.3 and 9.9 +/- 0.7 days in LR and CD recipients, respectively, whose grafts functioned immediately. Delayed graft function prolonged onset of reticulocytosis to 15.9 +/- 0.9 days in ALG-treated but not in CsA-treated recipients (5.8 +/- 0.4 days). The shortest latency was noted in CsA-treated recipients (4.9 +/- 0.5 days) with immediately functioning grafts. The earlier onset of reticulocytosis of CsA-treated recipients was followed by statistically significant blunting of peak reticulocytosis, which correlated with a slower rate of correction of anemia (delta Hct = 0.19/day) compared with non-CsA-treated recipients (delta Hct = 0.34/day). Early rejection was associated with abrogation of reticulocytosis and correction of anemia without regard to immunosuppressive regimen) until rejection was reversed. Erythropoietin (EPO) was measured sequentially in 5 patients with immediate function. In 4 of 5 cases changes in EPO preceded those in reticulocytosis. EPO rose from a mean of 13 mU/ml pretransplant to a peak of 50 within 3 weeks and decreased to 18 mU/ml within 6 weeks of graft implantation. At six months posttransplant, normalized reticulocyte counts were only 55% higher (1.75 vs. 1.13%) but hematocrit had increased from 26 +/- 1% to 42 +/- 1%. Hematocrit varied inversely with serum creatinine, which was highest in CsA-treated patients with initial delayed graft function. We conclude that correction of anemia posttransplantation is driven by EPO but other factors may also be important, that neither ATN nor ALG-therapy have clinically important effects on erythropoiesis, and that CsA reduced "effective" erythropoiesis and influences correction of anemia--particularly if delayed graft function complicates the initial course posttransplantation.

Antilymphocyte Serum↗