Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 30 patients with multiple myeloma (MM) and mild to moderate anaemia (mean Hb 107 g/l, 95% confidence limit (CL) 102-113) but no evidence of renal failure (serum creatinine < 110 mumol/l), serum erythropoietin (EPO) showed significant inverse logarithmic correlation with the haemoglobin level (r = -0.57, p = 0.001). The observed/expected ratio of log-EPO in patients with MM (mean 0.96, CL 0.89-1.04) was similar to that of 119 subjects (mean 1.01, CL 0.96-1.05) with or without anaemia (mean Hb 116 g/L, CL 110-121) but without renal failure. The concentration of circulating erythroid progenitors (BFU-E) in 10 MM patients in plateau phase was significantly reduced (mean 0.70 x 10(5)/l of blood, CL 0.34-1.06) compared to that of 8 normal controls (mean 3.57, CL 1.60-5.55, p = 0.011) In vitro sensitivity of the BFU-E to EPO in the patients with MM was comparable to that of the normal controls. It appears that in MM there is an appropriate EPO response to anaemia but even in the plateau phase the number of circulating BFU-E is reduced, reflecting a degree of marrow failure. However, the progenitors are normally sensitive to EPO in such patients, and therapeutic doses of EPO may correct the anaemia by a pharmacological rather than a physiological effect.
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PMID:Serum erythropoietin and circulating BFU-E in patients with multiple myeloma and anaemia but without renal failure. 847 97

Erythropoietin (Epo), the first growth factor to be discovered, is an endocrine hormone produced by specialized renal cells. The rate of Epo production is determined primarily by the oxygen demands of these renal cells relative to their oxygen supply. However, Epo production is modulated by various hormones, nutritional factors, cytokines, and the integrity of the erythron. Epo interacts with specific receptors found almost exclusively on erythroid progenitors. This interaction results in an expansion of the number of the erythroid progenitor and triggers late committed progenitors to undergo terminal maturation when provided with essential nutrients. Recombinant human Epo (rHuEpo) is commercially available for human use. It is safe, easily administered, and almost universally effective in treating the anemia of patients with renal failure. It has also been successful in treating the anemia of some patients with neoplasms, myelodysplastic syndromes, HIV infection, rheumatoid arthritis, and aplastic anemia. Much remains to be learned about the regulation of Epo production, the physiologic actions of Epo, and how best to use this growth factor in the treatment of anemia.
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PMID:Erythropoietin. 852 25

Recombinant human erythropoietin (r-HuEPO) is being successfully used for the treatment of uremic anemia. Several abnormalities of heme biosynthetic pathway have been described in patients with end-stage renal failure. In this condition, the activity of erythrocyte porphobilinogen deaminase has been found to be slightly increased. If this enzyme were to be the key enzyme in erythroid heme regulation, its activity would be increased to an even greater degree during the correction of uremic anemia. To assess this hypothesis, this study followed the variations of this and other parameters of porphyrin metabolism over 12 months of erythropoietin therapy in eight patients with nephrogenic anemia who underwent hemodialysis. By the first month of therapy, an increase of the previously depressed erythrocyte activity of aminolevulinate dehydratase was already evident, in coincidence with a nonsignificant increase of the reticulocyte count. The activity of this enzyme reached its maximal level by Month 3, and did not change up to Month 10. The porphobilinogen deaminase hyperactivity normalized at Month 4. By Month 12, in coincidence with the reduction of erythropoietin doses, the maximal levels of erythrocyte protoporphyrin, and the decrease in aminolevulinate dehydratase activity, the porphobilinogen deaminase values started to increase once again. In conclusion, the administration of r-HuEPO to hemodialyzed patients induced transient normalization of the previously observed porphyrin metabolism abnormalities. However, erythrocyte porphobilinogen deaminase activity did not rise concomitantly with the increase in hematocrit or hemoglobin values, but it did diminish during treatment. Therefore, porphobilinogen deaminase did not behave as a controlling enzyme in heme synthesis during the r-HuEPO-induced correction of uremic anemia.
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PMID:Effects of recombinant human erythropoietin on porphyrin metabolism in uremic patients on hemodialysis. 873 13

Chronic renal failure (CRF) is associated with a hyporegenerative anemia, which is caused primarily by inadequate production of erythropoietin (EPO) by the diseased kidneys and is responsive to exogenous EPO administration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations in vitro suggest an important role for insulin-like growth factor-1 (IGF-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, singly and in combination with EPO, in CRF in vivo. This study examined mice with surgically-induced renal failure of six weeks duration that were treated for three weeks with the combination of subtherapeutic doses of both EPO and IGF-1. The single administration of each cytokine caused no significant change in hemoglobin in all CRF mice. In marked contrast the combined administration of the two cytokines produced a striking rise in hemoglobin, resulting in anemia correction in the majority of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a dose-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in hemoglobin observed with the combination therapy indicates that these two cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum levels of low molecular weight binding proteins for IGF-1, potentially reducing the bioavailability of IGF-1. These findings taken together suggest that the anemia of CRF may represent both an EPO and a functional IGF-1 deficient state.
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PMID:Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse. 887 69

Recombinant erythropoietin (r-EPO) was administered to 37 patients with advanced, transfusion-dependent and chemo-resistant multiple myeloma (MM), at the fixed dose of 10,000/U s.c., 3 times a week, for 2 months. Thirteen patients (35.1%) achieved a significant response in terms of complete abolition of red cell transfusions. Factors significantly predictive of response were: a) inappropriate production of endogenous EPO, as expressed by a reduced observed/predicted ratio; b) presence of a consistent number of circulating erythroid precursors BFU-E; c) low serum levels of tumor necrosis factor (TNF) and interleukin-1 (IL-1), cytokines with inhibitory activity on erythropoiesis; d) a single line of previously received chemotherapy. Renal failure, bone marrow plasma cell infiltration, serum levels of IL-6 and other main clinical and laboratory parameters did not affect significantly the response to r-EPO. High fluorescence reticulocytes (HFR) and soluble transferrin receptor (sTfR) values were useful to detect an early stimulation of erythropoiesis in responders, while a high percentage of circulating hypochromic erythrocytes (HE), as assessed by an automated counter, identified those patients developing functional iron deficiency during r-EPO treatment. We conclude that about one-third of severely anemic patients with advanced MM, unresponsive to chemotherapy, may benefit by r-EPO therapy. The clinical management of these patients can be accomplished using non-invasive parameters, such as sTfR, HFR and HE.
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PMID:Clinical results of recombinant erythropoietin in transfusion-dependent patients with refractory multiple myeloma: role of cytokines and monitoring of erythropoiesis. 922 86

Jaundiced mice, ja/ja, suffer from a severe hemolytic anemia caused by a complete deficiency of erythroid beta-spectrin. We used these mice as a model to investigate the pathophysiological consequences of the deficiency, including the effects in the nonerythroid tissues where this protein is expressed. Because the ja/ja mice rarely survive beyond the fourth postnatal day, methods were assessed for extending lifespan into adulthood. Neonatal transfusion increased lifespan to a mean of 3.7 months, allowing a more complete characterization of the pathophysiology. Blood parameters and histopathology of the jaundiced mouse were compared with that from spherocytic mice, which have a hemolytic anemia caused by deficiency of erythroid alpha-spectrin, yet can survive the postnatal period transfusion free. The adult jaundiced and spherocytic mice present with greatly decreased hematocrit and red blood cell counts, reticulocytosis, and bilirubinemia, leading secondarily to hepatosplenomegaly and cardiomegaly. Jaundiced and spherocytic mice were analyzed histopathologically between 1.0 and 9.5 months of age. Interestingly, the complete absence of erythroid beta-spectrin in jaundiced mice leads to no detectable structural defects in brain, cardiac, or skeletal muscles. However, fibrotic lesions and lymphocytic infiltration were observed in cardiac tissue from 4 of 13 jaundiced mice and 15 of 15 spherocytic mice, and thrombi were detected at either the atrioventricular valves or within the atria of 2 of 13 jaundiced mice and 15 of 15 spherocytic mice. In addition, all affected mice had a progressive renal hemosiderosis concurrent with hydronephrosis and glomerulonephritis. The severity of the renal disease and its presence in all moribund mice suggests kidney failure rather than the fibrotic heart lesions as the major cause of death in these mice.
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PMID:Thrombosis and secondary hemochromatosis play major roles in the pathogenesis of jaundiced and spherocytic mice, murine models for hereditary spherocytosis. 937 73

Recombinant human erythropoietin is used in clinical practice mainly for treatment of anemia of renal failure. In the past years, however, its use has been approved for other indications, including prevention of anemia in surgical patients or in patients undergoing platinum-based chemotherapy, treatment of anemia of prematurity, of anemia induced by zidovudine therapy in HIV-infected patients, and of anemia induced by chemotherapy of nonmyeloid malignancies. Erythropoietin should routinely be given subcutaneously to maximize its effects. Most patients undergoing rHuEpo treatment develop functional iron deficiency, a situation in which iron supply to the erythroid marrow is inadequate for the erythrocyte precursor demand. Iron supplementation should, therefore, be given to all individuals receiving rHuEpo except for those patients with increased serum iron and transferrin saturation. Outside the setting of uremia, only a portion of patients can clearly benefit from erythropoietin therapy; therefore, the use of rHuEpo should be individualized in nonrenal applications.
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PMID:How and when to use erythropoietin. 957 Jul 2

We investigated the in vitro erythroid progenitor growth and the effects of sera on normal-marrow CFU-E (colony-forming units - erythroid) growth in 2 patients with renal failure on regular hemodialysis following a prior history of polycythemia vera (PV). PV was diagnosed 3 and 11 years, respectively, before the development of terminal renal failure. One of the patients had entered a spent phase of PV as characterized by diffuse extensive myelofibrosis and anemia; the other also had mild myelofibrosis. The serum erythropoietin (EPO) levels were low or normal on serial measurements by radioimmunoassay. There was no correlation between the hematocrit values and serum EPO levels. EPO-independent erythroid colonies were present in the cultures of bone marrow and peripheral blood cells from both patients after renal failure in the anemic state. With the addition of various concentrations of EPO, the number of erythroid colonies increased as the concentrations of EPO increased which was in accordance with the clinical observation that 1 patient with postpolycythemic myeloid metaplasia partially responded to recombinant human EPO therapy. In the EPO-dependent CFU-E assay, normal-marrow CFU-E numbers supported by 10% of the patient sera were less than those by normal sera. In the absence of EPO in cultures, no erythropoietic activity was found in the patients' sera. Our study on uremic patients with underlying PV showed that the biologic characteristics of autonomous erythroid progenitor growth for PV persisted during the spent phase and after the development of terminal renal failure with anemia. The erythroid progenitors responded to EPO both in vitro and in vivo. Their sera exhibited an inhibiting effect on the growth of normal-marrow erythroid progenitors.
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PMID:End-stage renal disease following polycythemia vera: in vitro and in vivo response of erythroid progenitors to erythropoietin and effects of sera on normal erythropoiesis. 964 92

Erythropoietin (EPO) is the glycoprotein hormone that promotes differentiation of erythroid progenitor cells in bone marrow. The normal kidney produces EPO to maintain erythrocyte for oxygen supply. This hormone activity was found in the serum of anemic animals in the 1890s. Renal failure results in severe anemia because of reduced EPO production, therefore anemia patients expected EPO treatment for long time. However, this was difficult due to the limited amount of EPO. Many researchers have tried to isolate EPO since the 1950s. Finally Miyake and Goldwasser purified highly active EPO from the urine of aplastic anemia patients. Since then, the characteristics and structural information from the purified material accelerated the cloning of the EPO gene. Mammalian cells were essential to produce EPO, because EPO contains 40% carbohydrate that plays some important roles in its activity, stability and biosynthesis. In 1984, two groups succeeded in cloning the EPO gene and expressing this gene in mammalian cells. Recombinant human EPO is currently available for anemia treatment. In this paper, we review production in mammalian cells, molecular characterization, especially carbohydrate moieties, and clinical applications of recombinant EPO.
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PMID:The production of recombinant human erythropoietin. 970 92

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. This cytokine was cloned in 1985 and rapidly became used for treatment of anemia of renal failure, opening the way to the first clinical trials of a hematopoietic growth factor. The clonage of one chain of the Epo receptor followed in 1989, thereby opening the research on intracellular signal transduction induced by Epo. Epo is synthesized mainly by the kidney and the liver and sequences required for tissue-specific expression have been localized in the Epo gene. A 3'enhancer is responsible for hypoxia-inducible Epo gene expression. HIF-1 alpha and beta proteins bind to this enhancer. Gene regulation by hypoxia is widespread in many cells and involves numerous genes in addition to the Epo gene. The Epo receptor belongs to the cytokine receptor family and includes a p66 chain which is dimerized upon Epo activation; two accessory proteins defined by cross-linking remain to be characterized. Epo binding induces the stimulation of Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. Furthermore, target disruption of both Epo and Epo receptor showed that Epo was not involved in the commitment of the erythroid lineage and seemed to act mainly as a survival factor.
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PMID:Biology of erythropoietin. 979 57


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