Erythropoietin Deficiency Research Articles

Decreased Erythropoietin Response in Patients with the Anemia of Cancer

Patients with solid tumors are often anemic even before they undergo cytotoxic therapy. Since the cause of the anemia of cancer is unknown, we examined the possible role of erythropoietin. Using a sensitive radioimmunoassay, we determined serum immunoreactive erythropoietin levels in 81 anemic patients with solid tumors. For any given degree of anemia, the serum concentration of immunoreactive erythropoietin was lower in this group of patients than in a group of control patients with iron-deficiency anemia (P = 0.0001). Furthermore, the expected inverse linear relation between serum levels of immunoreactive erythropoietin and of hemoglobin was absent in the group with cancer. The erythropoietin response was further decreased in patients receiving chemotherapy; it was not influenced by the presence or absence of cisplatin in the treatment regimen. The inability of the patients with cancer to produce erythropoietin was not absolute; if they had hypoxemia, adequate erythropoietin production was restored. We conclude that erythropoietin levels are inappropriately low in anemia associated with cancer, and that erythropoietin deficiency may contribute to the development of this form of anemia. Treatment of the anemia of cancer with erythropoietin may be of value.

Erythropoietin deficiency in acute tubular necrosis

Serum erythropoietin (EPO) concentrations were markedly depressed relative to the degree of anaemia in 10 patients with acute tubular necrosis, and remained low long after restoration of excretory renal function as estimated by glomerular filtration rate. Evidence is presented that the low serum EPO level is due to defective synthesis and not to increased catabolism. It is suggested that the predominantly are generatory anaemia found in prolonged cases of acute tubular necrosis, and the slow restoration of red cell mass during recovery, are due to the deficient synthesis of EPO. A positive erythropoietic response in a therapeutic trial with recombinant human erythropoietin (rhEPO) appears to support this hypothesis.

Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group.

To determine whether recombinant human erythropoietin improves the quality of life and exercise capacity of anaemic patients receiving haemodialysis. A double blind, randomised, placebo controlled study. Eight Canadian university haemodialysis centres. 118 Patients receiving haemodialysis aged 18-75 with haemoglobin concentrations less than 90 g/l, no causes of anaemia other than erythropoietin deficiency, and no other serious diseases. Patients were randomised to three groups to receive placebo (n = 40), erythropoietin to achieve a haemoglobin concentration of 95-110 g/l (n = 40), or erythropoietin to achieve a haemoglobin concentration of 115-130 g/l (n = 38). Erythropoietin was given intravenously thrice weekly, initially at 100 units/kg/dose. The dose was subsequently adjusted to achieve the target haemoglobin concentration. All patients with a serum ferritin concentration less than 250 micrograms/l received oral or intravenous iron for one month before the study and as necessary throughout the trial. Scores obtained with kidney disease questionnaire, sickness impact profile, and time trade off technique; and results of six minute walk test and modified Naughton stress test. The mean (SD) haemoglobin concentration at six months was 74 (12) g/l in patients given placebo, 102 (10) g/l in those in the low erythropoietin group, and 117 (17) g/l in those in the high erythropoietin group. Compared with the placebo group, patients treated with erythropoietin had a significant improvement in their scores for fatigue, physical symptoms, relationships, and depression on the kidney disease questionnaire and in the global and physical scores on the sickness impact profile. The distance walked in the stress test increased in the group treated with erythropoietin, but there was no improvement in the six minute walk test, psychosocial scores on the sickness impact profile, or time trade off scores. There was no significant difference in the improvement in quality of life or exercise capacity between the two groups taking erythropoietin. Patients taking erythropoietin had a significantly increased diastolic blood pressure despite an increase in either the dose or number of antihypertensive drugs used. Eleven of 78 patients treated with erythropoietin had their sites of access clotted compared with only one of 40 patients given placebo. Patients receiving erythropoietin were appreciably less fatigued, complained of less severe physical symptoms, and had moderate improvements in exercise tolerance and depression compared with patients not receiving erythropoietin. At the doses used in this trial there was a higher incidence of hypertension and clotting of the vascular access in patients treated with erythropoietin.

Erythropoietin Deficiency in Acute Renal Failure

Erythropoietin (Epo) was sequentially measured by radioimmunoassay in 11 patients with acute renal failure (ARF) of varied aetiology. Epo rapidly decreased to a level inappropriately low for the haemoglobin, the reduced Epo value persisting throughout the oliguric phase and for up to 2 weeks after the restoration of apparently normal renal function. Epo values found in ARF were: at referral 18.2 +/- 9.5, mid-oliguria 14.4 +/- 6.8, diuresis 15.6 +/- 5.8, and recovery 25.1 +/- 15.8 mU/ml. Results are compared with 34 patients with end-stage chronic renal failure, 42 with non-renal anaemia, and 96 normal subjects. Epo deficiency alone is an inadequate explanation of the rapid reduction in haemoglobin at the onset of ARF, but would appear to be an important factor in the maintenance of anaemia in prolonged ARF and accounts for the slow increase in haemoglobin following recovery.

Hematologic aspects of renal insufficiency

Renal dysfunction gives rise to a variety of hematologic disturbances, including anemia, leukocyte dysfunction, and coagulopathy. The anemia of renal failure has been attributed to a relative deficiency of erythropoietin, but contributing factors include an absolute deficiency of iron or folate. Other contributing factors include heavy metal toxicity, blood loss, and hemolysis. The treatment of the anemia of renal disease has advanced with the development of recombinant human erythropoietin. At doses from 15–500 μg/kg triweekly in selected patients, normalization of hemoglobin is presently possible. Transfusion may still have a role in patients with renal disease, although more as preconditioning for renal transplantation. In non-HLA matched transplantation, donor-specific transfusion, as well as immunosuppressives, may exert some benefit in graft survival. The coagulopathy of renal disease consists of an acquired qualitative platelet defect best remedied by dialysis but also treated successfully by cryoprecipitate or DDAVP. Infectious complications of uremia include diminished leukocyte chemotaxis, phagocytosis, and bactericidal activity. Cell-mediated immune defects and hypogammaglobulinemia have also been described. The pathophysiology involved in the protean hematologic manifestations of uremia are discussed; additionally, we describe therapeutic recommendations to deal with anemia, bleeding and infectious complications of renal failure.

Recombinant human erythropoietin.

Erythropoietin is produced mainly by the kidneys and stimulates erythropoiesis in the bone marrow. Chronic renal failure is characterized by anemia, which is principally caused by erythropoietin deficiency. Recombinant human erythropoietin (r-hEPO) corrects the anemia of chronic renal disease and improves patient well-being, exercise tolerance, and cognitive function. The clinical pharmacology, efficacy, safety, and tolerance of r-hEPO are presented. Four major studies attest to r-hEPO's efficacy in the treatment of anemia of chronic renal disease and document potential toxicities of hypertension, iron deficiency, thrombosis, and bone pain. Careful attention to the extent of correction of the hematocrit, increased heparinization during hemodialysis therapy, and compliance with dietary restrictions may minimize the incidence and severity of adverse reactions. Resistance to r-hEPO may be due to iron deficiency, aluminum toxicity, or inflammation, including infection. Potential future uses of r-hEPO include the treatment of various other anemias, such as those seen in sickle cell anemia, rheumatoid arthritis, and autologous blood donation. Controlled clinical studies in these areas have not been reported.

Aluminum-Dependent Transfusions in Dialysis

To the Editor. —We read with interest the article by Crowley and coworkers1describing the results of a retrospective study on the transfusion practice of a large renal hemodialysis center. We believe that the nephrologist's major concern is the more intensely transfused patients who, although a minority, require the majority of transfusions (67%, in that study).1 We all look forward to the introduction in clinical practice of recombinant human erythropoietin, which will help our patients' bone marrow performance, but we must not forget that erythropoietin deficiency is not the only cause of anemia in hemodialysis patients, especialy intensely transfused ones. Crowley et al1do not mention a widely accepted cause of dialysis anemia: aluminum intoxication.2,3Assuming good control of aluminum levels in the dialysate, aluminum intoxication may occur in patients taking aluminum-containing gels to control hyperphosphatemia.4The anemia caused by aluminum poisoning is non— iron-deficient,

1574 MULTICENTER STUDY OF SERUM ERYTHROPOIETIN AND PTH LEVELS IN CHILDREN WITH CHRONIC RENAL FAILURE

The relative roles of erythropoietin (Ep) deficiency and PTH excess in the development of anemia in children with chronic renal failure (CRF) have been assessed. Serum Ep in 71 patients (PTS) was determined by radioimmunoassay (RIA). Seven were studied in the predialysis stage, 32 on hemodialysis, 16 on CAPD and 16 on CCPD. The mean serum Ep was 38.1±3.5 mu/ml with anemia of renal disease (predialysis and dialysis PTS) compared to 19.6±1.5 mu/ml in normals. However, when compared to 30 children with anemia of non-renal origin, the elevation in Ep (range 28.7-327 mu/ml) was significantly below that expected for the degree of anemia in these renal disease PTS. We also found a direct inhibitory effect of uremic serum on both immunologic and biologic activity of Ep itself. Co-incubation of Ep (50, 100, or 200 mu/ml) with uremic serum resulted in markedly lower RIA values for these three concentrations of Ep compared to normal serum. Biologic activity as assessed in the fetal mouse liver CFU-E assay was also decreased with uremic serum. Serum PTH levels, although elevated, did not correlate with the degree of anemia. In conclusion although relative Ep deficiency plays a primary role in the anemia of CRF other factors which alter Ep itself and inhibit erythroid progenitors appear to be involved.

Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency

AbstractErythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. The relative importance of erythropoietin (Ep) and inhibition of erythropoiesis in the anemia of chronic renal insufficiency has been investigated. Sixty patients with varying degrees of renal insufficiency, 40 normal subjects and 40 patients with anemia and normal renal function, were studied. Erythroid (CFU-E) and granulocytic (CFU-GM) progenitor cell colony formation were assayed in fetal mouse liver and human bone marrow cultures, respectively. Erythropoietin was measured by radioimmunoassay. Hematocrit and plasma creatinine concentration correlated with the degree of serum inhibition of CFU-E formation (r = 0.69, P < 0.001, and r = 0.62, P < 0.001, respectively). Serum erythropoietin levels in patients with renal insufficiency (34.4 ± 6.7 mU/ml) were slightly higher than normal values (23.1 ± 0.98 mU/ml), but showed no relationship to plasma creatinine, hematocrit, or inhibition of CFU-E formation. In contrast, serum erythropoietin concentrations increased exponentially as the hematocrit decreased below 32% (r = 0.61, P < 0.001), and CFU-E formation was stimulated by serum in anemia patients with normal renal function. Studies of granulopoiesis showed uremic sera supported in vitro CFU-GM growth more efficiently than sera from normal subjects. These results suggest that inhibition of erythroid, but not granulocytic, progenitor cell formation, in addition to a relative erythropoietin deficiency, are the primary factors responsible for the anemia of chronic renal failure.Déficit en érythropoïétine et inhibition de l'érythropoïèse au cours de l'insuffisance rénale. L'importance relative de l'érythropoiétine (Ep) et l'inhibition de l'érythropoïèse lors de l'anémie de l'insuffisance rénale chronique ont été étudiées. Soixante malades avec des degrés variables d'insuffisance rénale, 40 sujets normaux et 40 malades avec une anémie et une fonction rénale normale, ont été étudiés. La formation de colonies cellulaires souches érythroïde (CFU-E) et granulocytaire (CFU-GM) ont été mesurées dans du foie foetal de souris et dans des cultures de moelle osseuse humaine, respectivement. L'érythropoiétine a été mesurée par dosage radioimmunologique. L'hématocrite et la concentration plasmatique de créatinine étaient corrélées avec le degré d'inhibition sérique de la formation de CFU-E (r = 0,69, P < 0,001 ; et r = 0,62, P < 0,001, respectivement). Les niveaux d'érythropoïétine sérique chez les malades atteints d'insuffisance rénale (34,4 ± 6,7 mU/ml) étaient légèrement plus élevés que les valeurs normales (23,1 ± 0,98 mU/ml), mais il n'y avait pas de relation avec la créatininémie, l'hématocrite, ou l'inhibition de formation de CFU-E. A l'opposé, les concentrations d'érythropoïétine sérique s'élevaient exponentiellement au fur et à mesure que l'hématocrite diminuait en dessous de 32% (r = 0,61, P < 0,001), et la formation de CFU-E était stimulée par du sérum chez des malades anémiques avec une fonction rénale normale. Des études de la granulopoïèse ont montré que les sérums urémiques supportaient la croissance in vitro de CFU-GM de façon plus efficace que les sérums de sujets normaux. Ces résultats suggèrent que l'inhibition de formation de cellules souches érythroïdes et non granulocytaires, en plus d'un relatif déficit en érythropoïétine, sont les facteurs primaires responsables de l'anémie de l'insuffisance rénale chronique.

Die Rolle des Erythropoietinmangels in der Pathogenese der renalen An�mie

A review is given of clinical studies performed by use of a highly sensitive in-vitro erythropoietin assay (fetal mouse livercell culture) in large patients' populations to clarify the controversial role of erythropoietin deficiency in the pathogenesis of renal anemia. Studies involved a.) patients with chronic renal disease and varying degree of renal insufficiency in the predialysis phase b.) non-nephrectomized and anephric patients on regular hemodialysis treatment. The data available demonstrate that the initial phase of renal anemia is accompanied by a compensatory increase of serumerythropoietin concentration and therefore erythropoietin deficiency has to be excluded as a primary cause of the anemia of renal failure; merely a relative lack of erythropoietin seems to exist. In the terminal phase of renal failure, erythropoietin deficiency becomes absolute, such in 50% of the investigated non-nephrectomized hemodialysis patients and in all anephric patients. However in individual patients even in terminal renal failure a sustained regulatory feedback mechanism between serumerythropoietin concentration and hematocrit, probably working at lower hematocrit level, could be demonstrated.

Investigations on latent erythropoietin (ESF) deficiency in non anemic patients with chronic renal disease using hypoxic stimulation methods.

So far the question has not been elucidated whether latent ESF-deficiency exists in patients with chronic renal disease during initial development of renal anemia. Therefore, ESF was determined in urine and serum of non anemic patients being exposed to acute hypoxia: 8 healthy volunteers and 8 patients who had a Ccreat below 48 ml/min were studied while in a hypobaric chamber for 4 subsequent periods of 10 h each (simulated maximal altitude 4000 m INA = 462 mm Hg). We also determined plasma iron turnover and reticulocyte counts. 10 h after the study began, the patients showed a significantly higher ESF-level than the normal volunteers. In the course of 48 h collection periods of urine under hypoxic conditions the mean ESF excretion in patients corresponded to 9.9 and in healthy persons to 7.3 Units. With regard to plasma iron turnover and reticulocyte count an increase was shown, but no significant differences existed between the two groups. A latent ESF-deficiency as the initial cause of renal anemia does not exist.

Serum erythropoietin concentration in anephric patients.

In 13 bilateral nephrectomized patients serum erythropoietin (SEp) activity could be measured quantitatively by use of the highly sensitive fetal mouse liver cell assay. SEp concentration in the majority of the cases was below the mean of normal controls. There was a significant positive correlation between SEp levels and hematocrits, suggesting erythropoietin (Ep) deficiency to be a causative factor in the anemia of the anephric state. Androgen therapy stimulated extrarenal Ep production in all of 5 anephric patients studied.

The Effect of Thiamphenicol on the Production of Immature Red Blood Cells under Anaemic Conditions

Summary. The toxic action of thiamphenicol was demonstrated in normal and phlebotomized rabbits. Thiamphenicol administration to normal rabbits resulted in a reduction of the number of reticulocytes and eventually to a decrease in the total red cell count. In rabbits made anaemic thiamphenicol did not prevent a reticulocyte crisis. The rate of synthesis of haemoglobin and the total amount of ribosomes in these reticulocytes were low. The disome was the most abundant polysome. This was in contrast with the findings of reticulocytes from control rabbits. Shortly after the thiamphenicol administration reticulocytes appeared with propcrties comparable with those from control rabbits.Besides the impairment of reticulocyte production a decrease in the total cellularity of the marrow was shown. The erythroid, granuloid and lymphoid cell lines appeared to be all affected. However, only the red cells showed a distinct shift from young to old erythroblasts. The inhibition of red cell production was not caused by a deficiency of erythropoietin since the levels were extremely high during thiamphenicol administration. From these findings it is concluded that one of the major effects of thiamphenicol is the inhibition of the conversion of the committed stem cell to proerythroblasts.

Fetal development in experimental uremia.

Uremic women on hemodialysis with metabolic bone disease (hyperparathyroidism, osteomalacia resulting from defective vitamin D metabolism) and anemia (erythropoietin deficiency) are known to give birth to infants without bone disease or anemia. Therefore, skeletal development (enchondral and desmal bone formation) and hepatic erythropoiesis were evaluated in fetuses of uremic rats. These fetuses failed to show defective mineralisation or evidence of bone disease. Bolus injection of high doses of exogenous PTH into the maternal or fetal organism did not affect fetal bone histology. In addition, no apparent defect of bone mineralisation or bone formation was found in fetuses of ricketic rats. Normal mineralisation in the offspring of uremic rats may be explained by fetal hyperphosphatemia and/or insensitivity of fetal (woven) bone mineralisation to vitamin D. Absence of fetal anemia (normal hematocrits, normal density of hematopoietic cells in the liver) in the presence of maternal anemia is presumably due to the insensitivity of fetal erythropoiesis to erythropoietin.

Infants and children with haematological disease

Infants and children with haematological disease

HUMORAL REGULATION OF ERYTHROPOIESIS. XII. EFFECT OF ERYTHROPOIETIN AND IRON ON CELL SIZE IN IRON DEFICIENCY ANEMIA.

SummaryErythropoietin did not affect the size distribution curve of iron deficient animals even when given in high doses. The type of erythroid response occurring after treatment with iron was related to the dose of iron administered, a macrocytic response being evoked after high doses and a normocytic response after low doses. The mechanism of action of erythropoietin and its relationship to available iron is discussed and a hypothesis presented to explain the above observations.