losartan-potassium and Uremia

Because kidneys consume a large amount of oxygen and are relatively inefficient in oxygen uptake, they are susceptible to hypoxia, especially in patients with advanced chronic kidney disease accompanied by loss of peritubular capillaries. Accumulating evidence suggests that chronic tubulointerstitial hypoxia acts as a final common pathway leading to end-stage renal disease. Some biologically active uremic retention molecules, considered as uremic toxins, accumulate as the renal function declines, and at this moment, more than 90 bioactive uremic toxins have been identified. Uremic toxins per se have been proven to accelerate the progression of renal failure. However, the causal relationship between uremic toxin and tubulointerstitial hypoxia remains unclear. Our studies provided direct evidence that uremic toxin dysregulates oxygen metabolism in the kidney. Indoxyl sulfate (IS), a representative protein-bound uremic toxin, increased oxygen consumption in proximal renal tubules, decreased renal oxygenation, and consequently aggravated hypoxia in the remnant rat kidneys. The increase in tubular oxygen consumption by IS was dependent on sodium-potassium adenosine triphosphatase and oxidative stress. Our work also indicated a possible connection between IS and the desensitization of the oxygen-sensing mechanism in erythropoietin-producing cells, which may partly explain inadequate erythropoietin production in hypoxic kidneys of end-stage renal disease patients. Studies of uremic toxins will open a new avenue in development of novel therapeutic approaches of kidney disease.

Topics: Animals; Cell Proliferation; Erythropoietin; Homeostasis; Humans; Hypoxia; Indican; Kidney; Kidney Failure, Chronic; Kidney Tubules; Oxidative Stress; Oxygen Consumption; Rats; Uremia

Multiple and complex abnormalities of hemostasis are revealed by laboratory tests in such common diseases as cirrhosis and end-stage renal insufficiency. Because these abnormalities are associated with a bleeding tendency, a causal relationship is plausible. Accordingly, an array of transfusional and nontransfusional medications that improve or correct these abnormalities is used to prevent or stop hemorrhage. However, recent data indicate that the use of hemostatic drugs is scarcely justified mechanistically or clinically. In patients with uremia, the bleeding tendency (mainly expressed by gastrointestinal bleeding and hematoma formation at kidney biopsy) is reduced dramatically by the improvement of anemia obtained with the regular use of erythropoietin. In cirrhosis, the most severe and frequent hemorrhagic symptom (acute bleeding from esophageal varices) is not explained by abnormalities in such coagulation screening tests as the prothrombin and partial thromboplastin times, because formation of thrombin the final coagulation enzyme is rebalanced by low naturally occurring anticoagulant factors in plasma that compensate for the concomitant decrease of procoagulants. Rebalance also occurs for hyperfibrinolysis and platelet abnormalities. These findings are consistent with clinical observations that transfusional and nontransfusional hemostatic medications are of little value as adjuvants to control bleeding in advanced liver disease. Particularly in uremia, but also in cirrhosis, thrombosis is becoming a cogent problem.

Topics: Anemia; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Coagulants; Erythropoietin; Fibrosis; Hemorrhage; Hemostasis; Humans; Kidney Diseases; Liver Diseases; Partial Thromboplastin Time; Risk Factors; Uremia

The use of erythropoietin (EPO) has revolutionized the treatment of anaemia associated with many conditions including chronic kidney disease (CKD). However, little is known of the cellular impact of EPO on the uraemic heart. The discovery that the EPO receptor (EPOR) is also expressed on non-haematopoietic cells including cardiomyocytes highlights a role of EPO beyond haematopoiesis. Animal models of heart failure have shown EPO can potentially reverse cardiac remodelling and improve myocardial function. Damage to the kidney, during uraemia, results in a decreased EPO production, which may render the uraemic heart more susceptible to damage and heart failure. Here we review current data on the cellular actions of EPO in models of left ventricular hypertrophy and heart failure and highlight parallels with the uraemic heart.

Topics: Cardiomyopathies; Erythropoietin; Fibrosis; Humans; Hypertrophy, Left Ventricular; Myocardium; Receptors, Erythropoietin; Risk Factors; Signal Transduction; Uremia; Ventricular Remodeling

Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.

Topics: Deamino Arginine Vasopressin; Erythropoietin; Estrogens, Conjugated (USP); Evidence-Based Medicine; Factor VIII; Fibrinogen; Hemorrhage; Humans; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency; Uremia; von Willebrand Factor

Anemia is a common complication of chronic kidney disease. Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic kidney disease are usually within the normal range and thus fail to show an appropriate increase with decreasing hemoglobin levels, as found in nonrenal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system. However, despite much progress in understanding the molecular mechanisms through which cells can sense oxygen availability and translate this information into altered gene expression, the reason why EPO production is inappropriately low in diseased kidneys remains incompletely understood. Both alterations in the function of EPO-producing cells and perturbations of the oxygen-sensing mechanism in the kidney may contribute. As with other anemias, the consequences of renal anemia are a moderate decrease in tissue oxygen tensions and counterregulatory mechanisms that maintain total oxygen consumption, including a persistent increase in cardiac output.

Topics: Anemia; Animals; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Hypoxia-Inducible Factor 1; Inflammation; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Receptors, Erythropoietin; Uremia

Uraemic patients are exposed either to iron deficiency due to impaired digestive n associated with various blood losses (particularly in dialysis patients) or iron verload related to blood transfusions in the pre-erythropoetin era or excessive intravenous iron supplementation. The central role of hepcidin in the regulation of oral iron absorption d its effects in uraemia have been recently evidenced. The increased haemoglobin synthesis induced by erythropoiesis stimulating agents (ESA) enhances iron requirements. In case of exhaustion of tissue reserves and/or insufficient exogenous supply, iron deficiency develops which is the major limiting factor for ESA efficacy. Careful biological follow-up is mandatory to detect early iron deficiency or overload, the latter being considered as possibly increasing the uraemic patients' susceptibility to bacterial or viral infections. Intravenous administration of Vitamin C, by enhancing the release of iron from the reticuloendothelial system towards transferrin increases the circulating iron available for erythropoiesis and contributes to the optimisation of ESA efficacy.

Topics: Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Ascorbic Acid; Erythropoietin; Hepcidins; Humans; Intestinal Absorption; Iron; Iron Deficiencies; Uremia

Several factors are involved in conditioning renal anemia, and a critical role is attributed to parathyroid hormone (PTH) oversecretion, which has some direct effects on endogenous erythropoietin (EPO) synthesis, bone marrow erythroid progenitors, and red cell survival. Indirect effects are mainly based on the induction of bone marrow fibrosis. Indirect evidence of the role of PTH is based on the observation that parathyroidectomy, when performed in uremic patients, is often followed by restoration of the hematocrit. The interpretations of such positive results are based on the observation of the restored bone marrow space after operation and also in a rise of immunoreactive EPO serum concentrations observed in the first weeks after gland removal. Another field of clinical interest is the possible beneficial effects of vitamin D therapy in controlling PTH secretion, which in turn determines an improvement of anemia of uremic subjects. Several uncontrolled studies confirmed this possibility, indicating that patients who respond to calcitriol or its analogs also show an increase of their hemoglobin levels. Thus, a combined therapeutic approach to PTH oversecretion and anemia is possible by intravenous calcitriol or parathyroidectomy pointing to the possible reversibility of bone marrow fibrosis, which is a common feature of secondary hyperparathyroidism. The increased sensitivity to EPO therapy can also induce a successful reduction of its dosage, thus allowing an interesting reduction of costs.

Topics: Anemia; Bone Marrow; Erythropoiesis; Erythropoietin; Fibrosis; Humans; Hyperparathyroidism; Parathyroid Hormone; Parathyroidectomy; Uremia; Vitamin D

Topics: Animals; Cat Diseases; Cats; Congresses as Topic; Diet, Protein-Restricted; Dietary Supplements; Erythropoietin; Recombinant Proteins; Uremia

Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Hyperparathyroidism; Hypoglycemic Agents; Insulin Resistance; Phosphoric Diester Hydrolases; Pyrophosphatases; Recombinant Proteins; Renal Dialysis; Thiazoles; Thiazolidinediones; Uremia

Patients receiving epoetin therapy show wide variability in their responsiveness to the drug. Many factors may be responsible for this, particularly iron deficiency, acute infection and under-dialysis. Even after excluding factors known to cause resistance to epoetin, the marked variability in sensitivity to epoetin remains. The exact mechanism of this effect is unclear. It is, however, recognized that uraemia is a chronic inflammatory state, with some patients showing quite significantly increased laboratory markers of inflammation and immune activation. It is also known that chronic inflammation can modify the process of erythropoiesis, and this is probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). It is hypothesized, therefore, that some patients showing resistance to epoetin may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. This has been investigated by studying T-cell phenotypes by flow cytometry, along with cytokine release from T cells and monocytes in 'good' and 'poor' responders to epoetin. Poor responders were found to have significantly reduced CD28 expression on both CD4(+) and CD8(+) cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels and enhanced TNF-alpha release from PBMCs. The patients in this study, who were followed-up for the subsequent 24 months, had a considerably lower survival if they were poor responders (54% vs 88% for good responders; P<0.05). Further work in this area is required to confirm or contest the hypothesis that epoetin resistance is due to enhanced levels of immune activation.

Topics: Drug Resistance; Erythropoiesis; Erythropoietin; Humans; Inflammation; Models, Biological; Recombinant Proteins; Uremia

Topics: Aged; Anemia; Chronic Kidney Disease-Mineral and Bone Disorder; Clinical Trials as Topic; Disease Progression; Electrolytes; Epidemiologic Methods; Erythropoietin; Hemodialysis Solutions; Humans; Hypertension; Kidney Failure, Chronic; Male; Models, Biological; Nutrition Disorders; Quality of Life; Renal Dialysis; Toxins, Biological; Uremia

Novel erythropoiesis stimulating protein (NESP, also known as darbepoetin alfa) is a molecule that stimulates erythropoiesis by the same mechanism as both native and recombinant human erythropoietin (rHuEPO). The extra sialic residues on NESP, however, allow it to be more stable in vivo with a 2- to 3-fold longer elimination half-life. Thus, following intravenous administration, the mean elimination half-life of NESP is 25.3 vs 8.5 h for rHuEPO. After subcutaneous administration, the mean terminal half-life for NESP is 48.8 h. The mean bioavailability of NESP after subcutaneous administration is approximately 37%, similar to that reported for rHuEPO. The pharmacokinetic data suggested that patients with renal anaemia would require less frequent dosing with NESP than with rHuEPO. NESP 0.45 microg/kg administered once weekly either intravenously or subcutaneously has been evaluated for the correction of chronic renal failure (CRF)-associated anaemia. The study population included CRF patients not receiving dialysis, along with those on haemodialysis or peritoneal dialysis. In patients who are rHuEPO-naïve, NESP has a similar effect in correcting the anaemia as is seen with rHuEPO, but with less frequent dosing. Similarly, in patients previously receiving rHuEPO, NESP (whether administered intravenously or subcutaneously) is as effective as rHuEPO treatment for maintaining haemoglobin concentration when administered at a reduced frequency (i.e. either once weekly or once every other week). NESP is well tolerated, adverse effects are similar to those seen with rHuEPO, and no antibodies have been detected in >1500 patients exposed to NESP thus far.

Topics: Anemia; Biological Availability; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Replacement Therapy; Safety; Uremia

Topics: Anemia; Apoptosis; Erythropoietin; Hematocrit; Hemolysis; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Uremia

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Renal Replacement Therapy; Uremia

Historically, epoetin has been used to treat anaemia in patients already receiving renal replacement therapy. For many years, however, the results of early animal experiments raised considerable concern among nephrologists that disease progression would be accelerated if epoetin therapy were initiated in the predialysis phase of renal failure. In retrospect, it has become clear that the results of these early animal experiments were confounded by a concomitant and uncontrolled rise in blood pressure. In subsequent studies in rat models, antihypertensive treatment effectively prevented the adverse effect on disease progression. In addition, the results of several small observational studies and one large controlled study suggest that the glomerular filtration rate is not adversely affected in pre-dialysis patients treated with epoetin as long as blood pressure is well controlled. There are several observations, though not definitive, which suggest that disease progression may even be slower when anaemia is reversed. The benefits of early anaemia treatment with epoetin include increased exercise capacity and improved quality of life, cognitive function, and sexual function. Anaemia has also been identified as an important aetiological factor in the development of left ventricular hypertrophy. Whether pre-emptive treatment of anaemia is indicated in all pre-dialysis patients, or at least in those who develop progressive left ventricular hypertrophy, is currently under investigation.

Topics: Anemia; Animals; Disease Progression; Erythropoietin; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency; Time Factors; Uremia

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

Topics: Anemia; Anti-HIV Agents; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Chemotherapy, Adjuvant; Erythropoietin; Female; Humans; Male; Multiple Myeloma; Myelodysplastic Syndromes; Recombinant Proteins; Uremia; Zidovudine

Topics: Anemia; Animals; Arginine; Bleeding Time; Blood Platelets; Endothelium, Vascular; Enzyme Inhibitors; Erythropoietin; Guanidines; Hemorrhage; History, 18th Century; History, 20th Century; Humans; Isoenzymes; Kidney Failure, Chronic; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Succinates; Uremia

The target hematocrit to be achieved when treating anemia in hemodialysis patients with erythropoietin is controversial. Current evidence-based recommendations suggest a target hematocrit range of 33% to 36%. Small studies suggest that normalization of hematocrit with erythropoietin may benefit hemodialysis patients in terms of brain function, physical performance, quality of life, and prevention of progressive left ventricular dilatation. However a recent study of the effects of erythropoietin-induced normalization of hematocrit in hemodialysis patients with symptomatic heart disease has shown an increase in both mortality and the rate of vascular access thrombosis. Currently, normalization of hematocrit in patients with symptomatic heart disease is not recommended, nor is it possible to conclude that possible benefits of normalization of hematocrit will outweigh risks in hemodialysis patients without symptomatic heart disease.

Topics: Anemia; Cardiomyopathies; Cardiovascular Diseases; Clinical Trials as Topic; Cognition; Erythropoietin; Exercise; Hematocrit; Humans; Iron; Recombinant Proteins; Renal Dialysis; Uremia

The hormonal aberrations that occur with end-stage renal disease (ESRD) are presented in this review in relation to fertility and conception among women on dialysis. The imbalance in gonadotropin production in dialysis-dependent men and women is characterized by elevations in luteinizing hormone (LH). In women dialysis patients, the normal estradiol-stimulated LH surge does not occur, resulting in anovulation. In men dialysis patients spermatogenesis is impaired, and low testosterone levels cause elevated LH. Infertility in those with ESRD is a culmination of many factors, including impotence and loss of libido, anovulation, and an altered hormonal milieu. Despite these inhibitors of conception, women on dialysis can conceive; pregnancy has been reported in 1% to 7% of women on dialysis in survey studies. The influence of dialysis mode (hemodialysis v peritoneal dialysis), recombinant human erythropoietin (EPO), and dialysis adequacy on the likelihood of conception among patients of either sex on dialysis is unknown. Reduced sexual activity and interest has consistently been reported in the ESRD population. The reasons for this are complex and likely involve the effects of comorbid illnesses, overall health status, body image factors, and hormonal alterations. Nephrologists rarely discuss conception and contraception with their women dialysis patients. Greater attention to these issues is needed.

Topics: Adult; Contraceptive Agents; Erythropoietin; Female; Fertilization; Humans; Infertility; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Pregnancy; Recombinant Proteins; Renal Dialysis; Uremia

The optimal target haemoglobin during treatment with recombinant human erythropoietin (r-HuEPO) is still controversial. The impact of haemoglobin on cardiovascular function or survival, on physical performance and on medical rehabilitation have to be taken into consideration. Although currently there is no solid evidence to show that haemoglobin beyond that recommended by the ad hoc committee of the National Kidney Foundation improves survival, sound theoretical arguments can be offered for this proposition, particularly in cardiac patients. It is sensible to individualize the target haemoglobin and to avoid rapid correction of anaemia.

Topics: Anemia; Cardiovascular System; Erythropoietin; Exercise; Hemoglobins; Humans; Oxygen Consumption; Recombinant Proteins; Renal Dialysis; Uremia

Human recombinant erythropoietin (r-HuEpo) was introduced widely to the clinical practice more than ten years ago. In many countries belonging to Central and Eastern Europe (CEE) use of this drug was very delayed mainly due to the high costs of treatment. The aim of the presented study was to estimate actual possibilities of r-HuEpo administration in thirteen CEE countries. Survey was performed using especially prepared questionnaires including questions connected with r-HuEpo and filled out by the members of the Central and Eastern Advisory Board in Chronic Renal Failure. Below mentioned numbers of patients were under the control of the responders during performing the survey: on hemodialysis (HD) 1119, on peritoneal dialysis (PD) 205 and 1556 after renal transplantation (RT). Respectively in subsequent groups 53.5% (HD), 41.5% (PD) and 16.2 (RT) of patients were treated using r-HuEpo. Possibilities of treatment differs significantly between two groups of countries. In those with better developed economy (Croatia, Czech, Hungary, Macedonia, Poland, Slovakia, Slovenia, Yugoslavia) 60-70% of dialysed patients were given r-HuEpo and in the rest of countries (Bulgaria, Latvia, Lithuania, Romania, Russia) this drug was administered in 10-35% of patients. The most popular way of the r-HuEpo administration were subcutaneous injections (89.3%) comparing with only 10.7% of patients getting this important hormone intravenously. Average weekly dose of r-HuEpo was 71-90 IU/kg/week in so treated patients and 91-100 IU/kg/week in whom drug was administered i.v., in majority of patients two or three times weekly. Major part of responders tried to achieve as the optimal level of Hb 10-12 g/dl but simultaneously in 1/3 of centres only achieving of the Hb level 9-10 g/dl was possible. The general majority of responders were not satisfied with the obtained results and recognised economical constrains as the main reason of such a situation. These problems were more widely observed in predialysis patients, because only few of them were on r-HuEpo treatment. Side effects of this drug expressed rarely and main of them were development or acceleration of hypertension (16%) and thrombotic complications in the vascular access (8%). The main cause of hyporesponsiveness to drug was iron deficit despite of the adequate monitoring of responders were convinced that further avoiding of economical constrains would be benefit dialysis and predialysis patients. It is especially important

Topics: Drug Administration Schedule; Drug Utilization; Erythropoietin; Europe; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Transplantation; Patient Satisfaction; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Adult; Anemia; Blood Loss, Surgical; Blood Transfusion, Autologous; Cost-Benefit Analysis; Erythropoiesis; Erythropoietin; Feedback; Hematologic Diseases; Humans; Infant, Newborn; Iron Deficiencies; Kidney; Neoplasms; Recombinant Proteins; Uremia

In the past several years significant attention has been directed to the study of adynamic bone disease in uremic patients. Several reports have provided additional information about the prevalence of adynamic bone disease in different countries. It has now become clear that the pathogenesis of adynamic bone disease cannot be ascribed to one single aetiological factor, but rather to a host of complex factors. From recently published papers we have learned about the mechanism of downregulation of the parathyroid hormone/parathyroid hormone-related peptide receptor on osteoblast-like cells, which may be a very important step in the pathogenesis of adynamic bone disease. A provocative hypothesis attempts to link the widespread use of erythropoietin to the emergence of adynamic bone disease-lacking excessive aluminium accumulation. It appears from some studies that bone-specific alkaline phosphatase might become a valuable tool in differentiating high turnover from low/normal turnover bone disease; however, further studies are needed to establish the role of this marker in the diagnosis of adynamic bone disease. Several papers discussed the pros and cons of lowering the calcium concentration of the dialysate in order to prevent adynamic bone disease. The results of these studies help us to understand the pathogenesis and the clinical relevance of this lesion in attempts to provide better care for our patients.

Topics: Alkaline Phosphatase; Biomarkers; Bone Diseases; Calcium; Erythropoietin; Hemodialysis Solutions; Humans; Hypoparathyroidism; Parathyroid Hormone; Renal Dialysis; Uremia

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Toxins, Biological; Uremia

Splenic peliosis was identified at necropsy in a 62-year-old woman receiving continuous ambulatory peritoneal dialysis for end-stage renal failure, and erythropoietin therapy for uraemia and anaemia. The immediate cause of death was arrhythmia related to ischaemic heart disease, following an episode of intramuscular haematoma (secondary to platelet dysfunction). The unusual association between peliosis and renal failure, and possibly erythropoietin therapy, is discussed.

Topics: Anemia; Erythropoietin; Fatal Outcome; Female; Hematoma; Humans; Kidney Failure, Chronic; Middle Aged; Splenic Diseases; Uremia

This report reviews the features of erythropoietin (Epo) production after renal transplantation. Successful kidney transplantation leads to the correction of renal anaemia over an 8-10 week period. An early ineffective peak of serum Epo may occur when there is delayed graft function. A late peak follows the decrease in serum creatinine and this is associated with a rise in haemoglobin. Serum Epo returns to normal when the haematocrit reaches 32%. Acute early rejection causes a striking reduction in serum Epo and reticulocytosis. In some patients the haematocrit continues to increase after complete correction of anaemia, resulting in post-transplant erythrocytosis (PTE). PTE generally appears to be an idiopathic erythrocytosis independent of Epo secretion. A greater Epo sensitivity of erythroid progenitors has been suggested. Theophylline and angiotensin converting enzyme inhibitors, which attenuate Epo production, can be used to treat PTE. The second part of this report describes the possible impact of human recombinant Epo (rHuEpo) on renal transplantation. The avoidance of blood transfusion with rHuEpo should eliminate the initiation of anti-HLA sensitization in uraemic patients without previous pregnancy and prior allograft. In some but not all presensitized patients transfusion withdrawal may reduce the sensitization level. There is currently no evidence that the reversing of anaemia by rHuEpo in kidney recipients impairs early graft function. Our results suggest that treatment with rHuEpo prior to transplantation may prevent the appearance of PTE. rHuEPO will reverse anaemia in patients with a failing graft and severe anaemia with little risk of accelerating graft failure and adverse events.

Topics: Anemia; Blood Transfusion; Erythropoiesis; Erythropoietin; Female; Graft Rejection; HLA Antigens; Humans; Immunosuppression Therapy; Kidney Transplantation; Polycythemia; Pregnancy; Recombinant Proteins; Uremia

Erythropoiesis is controlled by different regulators. Interleukin 3, granulocyte-macrophage colony-stimulating factor and stem cell factor play regulatory functions in the early steps of erythropoiesis. Erythropoietin (Epo) is the main factor which acts positively on the last steps of the production of erythrocytes in mammals. Epo is specific for the erythroid progenitor cells and has only little effect on other cells. The target cells for Epo are the erythroid progenitors (BFUe and CFUe). Epo acts on these progenitors through surface receptors specific for Epo. Epo induces the proliferation and differentiation of erythroid progenitors leading finally to reticulocytes. During this process, certain conditions are required to permit this differentiation: progenitors must be present in sufficient numbers, the bone marrow environment must be normal, and nutrients such as folic acid, vitamin B12 and particularly iron must be available. Elemental iron is an absolute requirement for adequate haemoglobin formation. Indeed, in a normal adult, without any stimulation, the bone marrow synthesizes 4 x 10(14) molecules of haemoglobin per second, each molecule containing four atoms of iron, which roughly corresponds to 20 mg iron. On the other hand, erythropoiesis is negatively regulated by several cytokines. These are macrophage-derived cytokines, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta). All these factors are elevated in the inflammatory state and are implicated in the pathogenesis of anaemia of chronic disease. TNF-alpha has an inhibitory effect on erythroid progenitors either directly or mediated by interferon-beta (INF-beta). IL-1 inhibits erythropoiesis in vivo in mice and in vitro in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Animals; Cytokines; Drug Resistance; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; In Vitro Techniques; Iron; Mice; Recombinant Proteins; Uremia

Topics: Anemia; Erythropoietin; Humans; Hypertension; Recombinant Proteins; Uremia

The bleeding time is prolonged in anemic patients independent of their platelet count and is shortened by elevating the hematocrit. It is theorized that an increase in circulating red blood cells increases platelet radial movement and interaction with endothelium. Platelet dysfunction in uremia is well known but poorly understood. Anemia is one contributory factor; others may involve storage pool deficiency, increased vessel wall prostaglandin production, and abnormal platelet arachidonic acid metabolism. Ameliorating anemia with red blood cell transfusions has been shown to shorten the bleeding time without affecting other platelet function values. Recently, recombinant human erythropoietin has been shown to shorten the bleeding time, with a parallel rise in hematocrit level to 30%. Clinicians should be aware that a diminished hematocrit may contribute to the bleeding tendency already present in patients with thrombocytopenia.

Topics: Anemia; Bleeding Time; Blood Platelets; Erythropoietin; Hematocrit; Humans; Megakaryocytes; Platelet Adhesiveness; Thrombocytopenia; Uremia

Topics: Anemia; Animals; Calcitriol; Erythropoietin; Humans; Neutrophils; Phagocytosis; Protein Binding; Purines; Recombinant Proteins; Renal Dialysis; Uremia; Uric Acid

Topics: Anemia; Animals; Blood Pressure; Erythropoietin; Hematocrit; Humans; Kidney; Recombinant Proteins; Uremia

Recent studies showed that the blood BFU-E, when subtracted from the uremic milieu, normally responds to the stimulating factor produced by T lymphocytes. The serum of uremic patients inhibits the in vitro growth of normal BFU-E, however, the inhibition is almost completely reversed by hemodialysis. These data allow to understand why the therapy with erythropoietin relieves the anemia of CRF. Uremic T lymphocytes fail to stimulate the BFU-E growth. Normal T lymphocytes are inhibited by uremic serum and the hemodialysis does not correct the defect. Lymphopenia, decreased number of both T4 and T8 lymphocytes and low T4/T8 ratio were found in 50% of patients. Cimetidine was still able to increase the burst-stimulating activity of uremic T lymphocytes through inhibition of the suppressor T subset. In conclusion, one can say that in CRF T8 lymphocytes are normal and that uremic toxins decrease both number and function of T4 lymphocytes. The deficiency of BPA appears to significantly contribute to the pathogenesis of the anemia of CRF. The experience from our and other Institutions shows the effectiveness of the recombinant human erythropoietin in relieving the anemia of CRF, notwithstanding the hematological milieu is highly modified by uremia.

Topics: Anemia; Combined Modality Therapy; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Biological Transport; Electrolytes; Erythropoietin; Humans; Kidney; Renal Dialysis; Trace Elements; Uremia

The recent availability of Recombinant Human Erythropoietin (EPO) has radically stirred-up diagnosis and therapeutical approach of anemia in dialysis patients. By correcting anemia in a dose related manner in virtually all dialysis patients, clinical use of EPO has confirmed its remarkable efficiency. Correction of anemia marked by a rapid improvement in "well being" of patients is also objectively associated with the correction of most of the debilatating multiple organs dysfunction due to the uremic state. Hypertension is one of the more frequent and worrying complication associated with EPO therapy. Optimal use of EPO, integrating administration route and frequency of injections, will reduce the EPO doses needed and minimize cost and side-effects incidence. EPO represents a major advance in the treatment of chronic uremia. EPO opens a new therapeutic era offering for the first time a substitute to a kidney endocrine failure.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Uremia

The uremia of chronic renal failure (CRF) can alter brain electrophysiology and cognitive function, even in the well-dialyzed patient. The effect of uremia on brain function can be assessed by electrophysiologic techniques such as electroencephalogram (EEG), sensory-evoked potentials (EPs), and cognitive event-related potentials (ERPs), and through a series of neuropsychologic tests. Five tests have been used clinically to measure the speed and efficiency of cognitive functioning and include the following: Number Cancellation, Trailmaking Test, Symbol Digit Modalities Test, Rey Auditory Verbal Learning Test, and Controlled Oral Word Association Test. Test performance by patients with CRF is often below that of healthy controls. Auditory ERPs, a sensitive indicator of subtle changes in central nervous system (CNS) function in uremia, result in the generation of a P300 component wave that varies in amplitude and latency with patient variables such as attention and effort. Although dialysis tends to normalize P300 latencies, the waves remain somewhat prolonged in most patients. The anemia often observed in patients receiving chronic dialysis appears to aggravate uremic encephalopathy. This effect can be reversed when anemia is corrected following administration of recombinant human erythropoietin (epoetin). Improvement in P300 amplitudes, and, in some cases, decreases in P300 latencies correlated well with epoetin-induced increases in hematocrit levels. With the correction of anemia, that component of brain dysfunction not attributable to retention of uremic toxins can largely be reversed.

Topics: Anemia; Brain; Cognition Disorders; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

Topics: Anemia; Anemia, Hypochromic; Animals; Drug Hypersensitivity; Erythropoietin; Humans; Hyperkalemia; Hypertension; Peritoneal Dialysis, Continuous Ambulatory; Phosphates; Recombinant Proteins; Renal Dialysis; Seizures; Thrombosis; Uremia

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Liver; Recombinant Proteins; Uremia

Several factors contribute to the pathogenesis of anemia due to renal failure. Hypoproliferation of red cell progenitors may be caused partially by an inhibitory effect of some 'uremic toxins' whose existence certainly is very controversial. Iron deficiency due to gastrointestinal and dialysis-related blood losses and occasionally aluminum intoxication may interfere with the maturation of the erythron. Moderate hemolysis with shortening of red cell survival to some 50% of normal may be an additional factor. The main cause of anemia is, however, inadequate production of erythropoietin by the diseased kidney. This latter factor has now become amenable to treatment.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Renal Dialysis; Uremia

Topics: Anemia; Erythropoietin; Humans; Quality of Life; Recombinant Proteins; Uremia

Topics: Anemia; Erythropoietin; Humans; Renal Dialysis; Uremia

Topics: Blood Transfusion; Chronic Disease; Erythrocyte Transfusion; Erythropoietin; Humans; Purpura; Uremia

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Uremia

Topics: Anemia; Aspirin; Bleeding Time; Blood Platelets; Blood Transfusion; Cryoprotective Agents; Deamino Arginine Vasopressin; Erythrocyte Transfusion; Erythropoietin; Estrogens; Hemorrhage; Humans; Parathyroid Hormone; Platelet Adhesiveness; Platelet Aggregation; Thromboxane A2; Uremia; von Willebrand Factor

Topics: Aluminum; Angiotensin II; Chronic Kidney Disease-Mineral and Bone Disorder; Communicable Diseases; Erythropoietin; History, 20th Century; Humans; Insulin; Kidney Failure, Chronic; Renal Dialysis; Renin; Uremia; Vitamin D

Topics: Anemia; Erythropoietin; Hematopoietic Stem Cells; Humans; Kidney Failure, Chronic; Uremia

Topics: Erythropoiesis; Erythropoietin; Humans; Immunocompetence; Leukocytes; Renal Dialysis; Transfusion Reaction; Uremia

Topics: Anemia; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Folic Acid; Hemoglobins; Hemorrhage; Hemostasis; Humans; Hypersplenism; Iron; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Uremia; Vitamin B 12

PTH may participate in the genesis of the anemia of uremia through at least three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing fibrosis of bone marrow cavity. A possible fourth mechanism through which PTH may contribute to the anemia of uremia is its effect on platelets. PTH inhibits platelet aggregation [53] and, as such, may play an important role in the genesis of the bleeding tendencies and the consequent blood loss in uremia.

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Colony-Forming Units Assay; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hematopoietic Stem Cells; Hemolysis; Hemorrhage; Humans; Hyperparathyroidism, Secondary; In Vitro Techniques; Mice; Parathyroid Hormone; Uremia

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.

Topics: Anemia; Animals; Cells, Cultured; Erythropoietin; Hematocrit; Humans; In Vitro Techniques; Kidney Failure, Chronic; Liver; Mice; Uremia

Recent work from our laboratory on the mechanism of polypeptide hormone handling by the normal kidney and the pathogenesis of altered hormonal metabolism in renal failure is reviewed. The kidney extracts substantial amounts of low - and medium - molecular weight polypeptide hormones from the renal circulation by a process which probably involves both glomerular filtration plus luminal reabsorption and direct peritubular uptake, although the relative contribution of the two mechanisms under physiologic conditions is not known. The bulk of the extracted hormone is catabolized in the renal parenchyma since urinary excretion is negligible. Renal catabolism contributes an important fraction of the total metabolic clearance of polypeptide hormones, which accounts in part for their increased circulating levels in renal failure. Since certain hormones are heterogenous and a large proportion of their plasma immunoreactivity may consist of components of uncertain biologic activity, simple correlations between circulating hormone levels and endocrine abnormalities in uremia are hazardous.

Topics: Animals; Antigens; C-Peptide; Erythropoietin; Glucagon; Gonadotropins, Pituitary; Humans; Insulin; Kidney; Kidney Failure, Chronic; Luteinizing Hormone; Metabolic Clearance Rate; Molecular Weight; Pancreatic Hormones; Proinsulin; Prolactin; Uremia

The widespread and ever expanding use of dialysis in the maintenance of patients with chronic renal disease has added an urgency to the study of the biogenesis of erythropoietin. It seems almost certain that erythropoietin could ameliorate, if not eliminate, the anemia of uremia, but unfortunately, erythropoietin is still not available in therapeutic quantities. Initially, erythropietin was though to be produced by the kidneys" but then the attention became directed at the liver. It was proposed that erythropoietin was produced there as an inactive precursor and that the kidney only acted as an oxygen sensor and as a producer of an erythropoietin-activating enzyme. Recent studies summarized here show that an isolated perfused kidney in the absence of any extrarenal substrate or precursor can synthesize erythropoietin. Consequently, it appears almost certain that the kidney is the endocrine organ of origin of erythropoietin. Further studies suggest that erythropoietin formation involves a phase of oxygen sensing and programming and a phase of synthesis. These phases probably occur in the same cell, and the renal cortex appears to be the most likely location for such cells. The current inability to extract erythropoietin from kidney homogenates is discussed but, unfortunately, not adequately explained.

Topics: Animals; Erythropoietin; Humans; Hypoxia; Kidney; Kidney Cortex; Oxygen Consumption; Perfusion; Rabbits; Time Factors; Uremia

Anemia is a frequent complication of renal failure. As in anemias of other origin, the resulting tissular hypoxia is partially compensated by an increased production of 2,3-diphosphoglycerate in red cells and a shift to the right of the oxygen hemoglobin dissociation curve. Two mechanisms are implicated in this anemia: increased hemolysis and depressed production of red cells. Decreased production of erythropoietin is probably the cause of reduced erythropoiesis, but the role of uremic intoxication has not been unequivocally excluded. In the course of chronic hemodialysis, iron deficiency anemia and occasionally hypersplenism develop. It is noteworthy that blood requirements in anephric patients are two to three times greater than those of nonanephric hemodialyzed patients. Accordingly, bilateral nephrectomy should be restricted to carefully selected cases. At the present time, androgens seem to be the best treatment of renal anemia. Qualitative anomalies of platelets are the main factor responsible for uremic bleeding and are corrected by hemodialysis.

Topics: Anemia; Animals; Cell Survival; Erythrocytes; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hemolysis; Hemorrhagic Disorders; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Transplantation, Homologous; Uremia

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Cyclic AMP; Cytoplasm; Erythropoietin; Glomerulonephritis; Hematopoietic System; Humans; Liver; Polycythemia; Reticulocytes; RNA; Sheep; Spleen; Uremia

Topics: Adult; Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Platelets; Blood Urea Nitrogen; Bone Marrow Cells; Chronic Disease; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Feedback; Female; Hemolysis; Hemostasis; Humans; Hypertension, Malignant; Iron; Kidney; Kidney Concentrating Ability; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Oxygen Consumption; Plasma Volume; Uremia

Topics: Anemia; Blood Transfusion; Blood Urea Nitrogen; Chromium Isotopes; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Iron; Iron Isotopes; Kidney; Kidney Diseases; Polycythemia; Uremia

End-stage renal disease is a state of enhanced oxidative stress (OS) and hemodialysis (HD) and renal anemia further augment this disbalance. Anemia correction with erythropoietin (EPO) may improve oxidative status. However, there is no evidence of time dependent effects of EPO therapy on redox status of HD patients.. The aim of this study was to evaluate whether the duration of EPO treatment may affect OS parameters in uremic patients.. 104 HD patients and 29 healthy volunteers were included. Patients were divided into 3 groups according to the duration of EPO treatment. Forth group consisted of HD patients without EPO treatment. Plasma and erythrocyte malondialdehyde (MDA, MDA(rbc)), reactive carbonyl groups (RCG), plasma sulfhydryl (-SH) groups and total antioxidative capacity (TAC) levels were evaluated.. HD patients both with and without EPO treatment, showed a significant increase in all oxidative parameters without significance between EPO treated and -untreated group. The decrease in MDA and MDA(rbc) levels coincided with the duration of EPO treatment. A negative correlation was observed between the duration of EPO treatment and serum MDA (r=-0.309, p=0.003). Increasing periods of EPO treatment were associated with decrease in RCG, without significance between EPO groups. Increase in TAC accompanied increasing durations of EPO treatment, with EPO treatment for more than 24 months causing the most striking changes (p<0.05). There were no significant differences in -SH levels between EPO subgroups.. Our results suggest that long term administration of EPO attenuated the lipid peroxidation process and restored the levels of antioxidants.

Topics: Aged; Analysis of Variance; Anemia; Antioxidants; Cross-Sectional Studies; Drug Administration Schedule; Erythrocytes; Erythropoietin; Female; Humans; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Dialysis; Time Factors; Uremia

Hemofiltrate reinfusion (HFR) is a form of hemodiafiltration (HDF) in which replacement fluid is constituted by ultrafiltrate from the patient 'regenerated' through a cartridge containing hydrophobic styrene resin. Bicarbonate-based dialysis solutions (DS) used in routine hemodialysis and HDF contain small quantities of acetate (3-5 mM) as a stabilizing agent, one of the major causes of intradialytic hypotension. Acetate-free (AF) DS have recently been made available, substituting acetate with hydrochloric acid. The impact of AF DS during HFR on Hb levels and erythropoietic-stimulating agent (ESA) requirement in chronic dialysis patients was assessed.. After obtaining informed consent, 30 uremic patients treated by standard bicarbonate dialysis (BHD, DS with acetate) were randomized to treatment in 3-month cycles: first AF HFR, followed by HFR with acetate, and again AF HFR. At the beginning and end of each period, Hb and ESA requirements were evaluated.. A significant increase in the Hb level was observed throughout all periods of HFR versus BHD (from 11.1 to 11.86 g/dl; p = 0.04), with a significant decrease of ESA requirements from 29,500 to 25,033 IU/month (p = 0.04).. Regardless of the presence or absence of acetate in DS, HFR per se allows a significant lowering of ESA dosage versus BHD, while at the same time increasing Hb levels. Taking for granted the clinical impact produced, HFR seems to provide a relevant decrease in end-stage renal disease patient costs.

Topics: Aged; Aged, 80 and over; Cytokines; Dietary Supplements; Erythropoietin; Female; Hematinics; Hemodiafiltration; Hemodialysis Solutions; Hemoglobins; Humans; Male; Middle Aged; Treatment Outcome; Uremia; Vitamins

Although the general improvement caused by recombinant human erythropoietin (rHuEPO) in the correction of uraemic anaemia cannot be questioned, some data suggest that the changes in the haemostasis, endothelial function and oxidative stress (SOX) are induced. The aim of the present study was to investigate the effect of one-year rHuEPO therapy on the coagulation activation, endothelial injury markers and SOX in haemodialysis (HD) patients.. Assessment of coagulation activation pathway: tissue factor (TF), its inhibitor (TFPI) and prothrombin fragment 1+2 (F1+2); endothelial injury markers: von Willebrand factor antigen (vWF:Ag) and thrombomodulin (TM); and several parameters related to SOX: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies to oxidized LDL (OxLDL-Ab) levels were performed in stable HD patients, treated for 12 months with rHuEPO (n=18; mean dose 113.5+/-41 U/kg/week) or not (with Hg<10 g/dl, n=8 and with Hg>10 g/dl, n=12), none of them on iron therapy.. Patients with Hg<10 g/dl had a significantly lower erythrocytes count, Ht and Hg levels than those with Hg>10 g/dl and those on rHuEPO therapy. Long-term rHuEPO therapy does not affect coagulation pathway and SOX markers. Treatment with this hormone resulted in a tendency to decrease TM and vWF:Ag concentrations, however these changes did not reach a statistical significance.. These results suggest that one-year rHuEPO therapy seems to exert no additional influence on coagulation activation, endothelial cell damage/activation markers and oxidative stress in patients undergoing regular HD in the absence of concomitant iron supplementation and irrespective from haemoglobin levels.

Topics: Adult; Aged; Anemia; Biomarkers; Blood Coagulation; Endothelium, Vascular; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period.. We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH.. The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 +/- 26.4 vs. 9.8 +/- 7.4 ml/session, p < 0.05), frequency (0.60 +/- 0.26 vs. 0.10 +/- 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 +/- 56.4 vs. 104.8 +/- 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 +/- 0.9 vs. 7.9 +/- 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods.. The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Topics: Aged; Anemia; Antihypertensive Agents; Appointments and Schedules; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetic Nephropathies; Echocardiography; Erythropoietin; Female; Ferritins; Humans; Hypertension, Renal; Hypotension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Quality of Life; Recombinant Proteins; Renal Dialysis; Uremia

Haemodialysed patients are highly exposed to different virus infections namely hepatitis B (HBV) and C (HCV). Recently it was shown, that the use of recombinant human erythropoietin (rHuEPO) in haemodialysed patients with chronic renal failure (CRF) stimulates not only erythropoesis but also increases--in an indirect or direct manner--the humoral and cell--mediated immune defense. The aim of the present study was to determine the prevalence of HBV and HCV infection in haemodialysed patients with CRF and renal anaemia treated either with rHuEPO or with allogenic blood transfusions only. 32 patients with CRF and renal anaemia (haematocrit value below 28%) were included in this study at the early stage of the dialysis therapy (0 to 6 months from the first haemodialysis session). All patients were randomly allocated into two groups. The first one consisted of 15 haemodialysed patients treated with rHuEPO, the second group composed of 17 occasionally treated with blood transfusions (No-EPO group). In patients of both groups the following parameters were examined before (0) and after 3, 6, 9, 12 months of monitoring number of units blood transfused, hemoglobin concentration, serum levels of ferritin. Before the study (0) and after 6 and 12 months presence of antigen HBs (AgHBs), antibodies anti-HBc, anti-HBs, anti-HCV, DNA HBV and RNA HCV were examined. Before the study markers of HBV infection (DNA HBV and/or AgHBs and/or anti-HBc) were found in 46.7% of patients in EPO group and in 52.9% of patients in NO-EPO group respectively (NS). After six months of the study markers of HBV infection were present in 60% of patients in EPO group and in 76.5% of patients in No-EPO group (NS). After 12 months of dialysotherapy HBV infection markers were found in 66.7% patients in EPO group and in 76.5% of patients in No-EPO group (NS). Significantly higher prevalence of HBV infections were found after 6 and 12 months respectively in No-EPO group in comparison to the prestudy period (p < 0.05). At the beginning of the study markers of HCV infection (RNA HCV and/or anti-HCV) were present in 26.7% of patients in EPO group compared to 35.3% of patients in No-EPO group (NS). After 6 months of therapy markers of HCV infection were found in 26.7% of patients in EPO group and in 64.7% of patients in No-EPO group (p < 0.05). After 12 months of treatment markers of HCV infections were present in 40% of patients in EPO group and 76.5% of patients in No-EPO group (p < 0.05).ln patients. Treatment of renal anaemia with rHuEPO contributes to the significant decrease in prevalence of HCV infection. Decrease of prevalence of HCV infection in haemodialysed patients with chronic renal failure treated with rHuEPO seems to be predominantly a result of the complete cessation of allogenic blood transfusion. Blood transfusions seem not to be the main cause of HBV transmission in haemodialysed patients.

Topics: Adult; Anemia; Erythropoietin; Female; Hepatitis B; Hepatitis C; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Time; Uremia

Some parameters of extrinsic coagulation pathway, including concentration and activity of tissue factor and concentration of tissue factor pathway inhibitor, have been estimated in uremic hemodialysis patients. The impact of erythropoietin treatment on the extrinsic coagulation pathway has also been the aim of the study. Increased concentration of tissue factor pathway inhibitor--TFPI has been found both in dialysed and non-dialysed uremic patients. This finding may be the evidence of endothelial damage as well as the protective factor against thrombotic complications. Erythropoietin treatment seemed not to induce statistically significant changes in extrinsic coagulation pathway. Some results indicate that estimation of "truncated' and "full length" forms of TFPI may be more useful comparing to complete TFPI concentration.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Erythropoietin; Female; Humans; Lipoproteins; Male; Middle Aged; Renal Dialysis; Thromboplastin; Thrombosis; Treatment Outcome; Uremia

In hemodialysis patients, oxidative stress results from an imbalance between the production of reactive oxygen species and antioxidant defense mechanisms. Recently, a new dialysis multi-layer membrane has been developed, by modifying the inner surface of regenerated cellulose to support a vitamin E coating. The aim of our study was to investigate the effects of hemodialysis treatment with vitamin E-modified membrane on anemia and erythropoietin requirement in a group of chronic uremic patients. Ten uremic, non diabetic, patients on standard bicarbonate dialysis were treated with vitamin E-bonded dialysis membrane for 12 months. Hematological parameters, erythropoietin requirement, serum vitamin E and serum malonyldialdehyde (MDA) were evaluated before starting the study and monthly. No significant changes in hemoglobin level, RBC count, hematocrit and EPO requirement were observed. Basal vitamin E levels were in the normal range (13.0 +/- 2.88 mg/L vs. 14.79 +/- 3.12 mg/L; NS). On the contrary, basal MDA levels were higher than those observed in the control group (1.87 +/- 0.36 vs. 1.13 +/- 0.18 mmol/mL; p < 0.01) and a significant decrease of MDA levels was found after 1 month of Excebrane treatment (1.39 +/- 0.25 nmol/mL; p < 0.02). In conclusion, the role of the "oxidative hemolysis" in the pathogenesis of anemia in CHD patients is still not clearly defined, but it could be of minor clinical relevance. Although the effectiveness of vitamin E-coated membranes as a scavenger of ROS allows a better control of intradialytic oxidative stress, it doesn't seem to contribute to clinical management of anemia in these patients.

Topics: Adult; Aged; Anemia; Cellulose; Erythropoietin; Hematologic Tests; Humans; Lipid Peroxidation; Male; Malondialdehyde; Membranes, Artificial; Middle Aged; Oxidative Stress; Renal Dialysis; Uremia; Vitamin E

The aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF).. We monitored for 2 years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance < or =25 mL/min), randomized to either low protein diet (LPD) group (0.6 g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3 g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels.. The achieved protein intake after 6 months was 0.79 +/- 0.02 g/kg body weight/day and 0.50 +/- 0.02 g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 +/- 0.2 g/dL and 11.5 +/- 0.3 g/dL). EPO dose, that was similar at baseline (62.4 +/- 9.6 UI/kg body weight/week and 61.8 +/- 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 +/- 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 +/- 55 pg/mL to 118 +/- 16 pg/mL (P < 0.0001) in VLPD and did not change in LPD.. In patients with advanced CRF, an effective decrease of protein intake of 0.3 g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.

Topics: Adult; Aged; Anemia; Diet, Protein-Restricted; Dietary Proteins; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Compliance; Uremia

Oxidant stress has a pathogenic role in uremic anemia, possibly interfering with erythropoietin (EPO) function and red blood cell (RBC) survival. Therefore, it is expected that antioxidant therapy might exert a beneficial effect on these parameters.. To test this hypothesis, we investigated some oxidant stress indices, anemia levels, and RBC survival in 47 hemodialysis (HD) patients randomly assigned to three groups. Patients in groups A (n = l8) and B (n = 20) were on dialysis therapy using conventional cellulosic and synthetic membranes and were administered high and low doses of recombinant human EPO (rHuEPO), respectively. Patients in group C (n = 9) were dialyzed with vitamin E-modified membranes (CL-Es) and investigated in a two-step prospective study. In step Cl, patients were administered rHuEPO doses similar to those of group A. In step C2, rHuEPO doses were reduced to those of group B. As oxidant stress markers, we determined in plasma the susceptibility of lipids to undergo iron-catalyzed oxidation (reactive oxygen molecules [ROMs] test) and malondialdehyde-4-hydroxynonenal (MDA-4HNE), alpha-tocopherol (alpha-T), total thiol (-SH), and total antioxidant activity. RBC survival was measured using the chromium 51 T/2 technique in 22 patients.. Results show that: (1) high rHuEPO doses (groups A and C1) were associated with decreased ROM production, low alpha-T levels, and slightly increased -SH levels compared with corresponding groups on low rHuEPO doses (groups B and C2); (2) treatment with CL-Es (group C) increased plasma alpha-T and decreased -SH levels; these data were associated with decreased indices of lipid peroxidation, particularly MDA-4HNE 1evels, only in patients administered low rHuEPO doses; (3) alpha-T concentration influenced RBC survival, which was remarkably decreased in HD patients; patients treated with CL-Es showed a better degree of anemia correction; and (4) alpha-T level correlated negatively with -SH level and seemed to be independent of the extent of peroxidation and oxidizability of plasma lipids.. Both EPO and CL-E can influence plasma antioxidants and, to an extent, lipid peroxidation processes. However, this study shows that even in patients treated with low rHuEPO doses, RBC survival close to normal and sufficient correction of anemia are achieved only when appropriate alpha-T levels are reached.

Topics: Adult; Aged; Anemia; Antioxidants; Biomarkers; Cell Survival; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membranes, Artificial; Middle Aged; Oxidative Stress; Prospective Studies; Recombinant Proteins; Renal Dialysis; Uremia; Vitamin E

The kidney accumulates the highest level of selenium (Se) in the organism and is the major source of plasma glutathione peroxidase (GSH-Px). Se, as an integral part of the active site of GSH-Px, plays an important role in protecting cell membranes from oxidative damage. Decreased blood Se levels and GSH-Px activity are common in chronic renal failure (CRF) patients. Our study was an effort to evaluate the effect of erythropoietin (EPO) therapy and Se supplementation for CRF patients undergoing regular hemodialysis (HD) on blood Se, red cell glutathione (GSH), and blood lipid peroxidation product levels, and on blood activity levels of GSH-Px and blood superoxide dismutase (SOD).. Our subjects were divided into three groups: I - CRF patients on regular HD and EPO, II - HD patients receiving EPO and Se, and III - healthy controls. Se levels, SOD and GSH-Px activities were measured spectrofluorometrically, the GSH level by Beutler's colorimetric method, and lipid peroxidation products using TBARS.. EPO therapy with Se supplementation significantly increased whole blood and plasma Se in HD patients, and raised red cell GSH-Px activity, but plasma GSH-Px activity, plasma superoxide dismutase, and plasma and red cell TBARS did not respond to Se supplementation. EPO alone showed no effect on these parameters.. Treatment with EPO and supplementation with Se significantly increased the element concentration in whole blood and plasma, and GSH-Px activity in red cells. Plasma GSH-Px activity did not respond to Se.

Topics: Adolescent; Adult; Antioxidants; Dietary Supplements; Erythropoietin; Female; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Selenium; Spectrometry, Fluorescence; Time Factors; Uremia

Topics: Aged; Blood Platelets; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Recombinant Proteins; Uremia

To verify the therapeutical effect of exogenous reduced glutathione (GSH) on the patients with uremic anemia.. Forty two patients with uremic anemia were randomly divided into treatment group and control group. All patients received subcutaneously recombinant human erythropoietin (r-HuEPO) at the dose of 3000U twice a week for 12 weeks. Each of the patients in the treatment group was given intravenously reduced glutathione at the dose of 1200 mg twice a week for 12 weeks. The measurements of hemoglobin, red blood cells and hematocrit were performed.. After administration of r-HuEPO, the levels of hemoglobin, red blood cells and hematocrit were significantly elevated in both treatment and control groups (P < 0.01). The levels of hemoglobin, red blood cells and hematocrit in treatment group were elevated much more obviously, compared with those in control group (P < 0.05).. These findings seem to indicate that exogenous GSH could enhance the effect of r-HuEPO on uremic anemia, and therefore it might represent a useful drug in the treatment and management of uremic anemia.

Topics: Adult; Anemia; Drug Synergism; Erythropoietin; Female; Glutathione; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Impaired red blood cell-deformability (RBC-df) is noted in patients with diabetes and may play a role in the pathogenesis of microvasculopathy and nephropathy. We report the effects of erythropoietin (EPO) alone and combined with aminoguanidine (AG) for 1 year on RBC-df in predialysis patients (P-DPs) with renal insufficiency and in end-stage renal disease (ESRD) patients on maintenance hemodialysis (DPs). Nine P-DPs who received EPO 50 U/kg by subcutaneous injection 3 times per week are compared with 5 P-DPs treated without EPO (mean serum creatinine 4.1 +/- 0.1 versus 4.2 +/- 0.6 mg/dL, respectively). Twelve DPs (Kt/V = 1.5 +/- 0.1) were studied. Six DPs received AG 200 mg/every other day by mouth and EPO 50 U/kg by intravenous (IV) injection, and 6 DPs received EPO (50 U/kg) and placebo and served as control. RBC-df improved significantly in 9 P-DPs treated with EPO at 6 months (from 2.7 +/- 0.1 to 1.6 +/- 0.2, P = 0.005). This positive effect was sustained at 12 months (P = 0.005); there was no change in RBC-df in P-DPs receiving usual care without EPO. RBC-df improved significantly and progressively at 6 and 12 months in DPs treated with EPO and AG (from 2.2 +/- 0.2 to 1.8 +/- 0.2; P = 0.01; 1.2 +/- 0.1; P = 0.001, respectively); there was limited improvement in RBC-df in DPs treated with EPO and placebo. We conclude that EPO treatment significantly improved RBC-df in diabetic P-DPs, but EPO alone has no significant effect on RBC-df after 12 months in diabetic DPs. The combination of EPO and AG restores RBC-df to near-normal levels in diabetic DPs. We speculate that the effect of EPO on RBC-df seen in P-DPs and DPs is related to increased synthesis and influx of new and younger RBCs. AG may confer protection of RBCs in DPs by blocking advanced glycosylated end-product (AGE) formation.

Topics: Area Under Curve; Diabetic Nephropathies; Drug Therapy, Combination; Erythrocyte Deformability; Erythropoietin; Female; Guanidines; Hematocrit; Humans; Injections, Subcutaneous; Male; Middle Aged; Renal Dialysis; Uremia

Patients with chronic renal failure (CRF) often have reduced concentrations of selenium (Se) and lowered activities of glutathione peroxidase (GSH-Px) in blood components. The kidney is a major source of plasma GSH-Px. We measured Se and glutathione levels in blood components and red cell and plasma GSH-Px activities in 58 uremic patients on regular (3 times a week) hemodialysis (HD). The dialyzed patients were divided in 4 subgroups and were supplemented for 3 months with: 1) placebo (bakers yeast), 2) erythropoietin (EPO; 3 times a week with 2,000 U after each HD session), 3) Se-rich yeast (300 microg 3 times a week after each HD), and 4) Se-rich yeast plus EPO in doses as above. The results were compared with those for 25 healthy subjects. The Se concentrations and GSH-Px activities in the blood components of dialyzed uremic patients were significantly lower compared with the control group. Treatment of the HD patients with placebo and EPO only did not change the parameters studied. The treatment with Se as well as with Se and EPO caused an increase in Se levels and red cell GSH-Px activity. Plasma GSH-Px activity, however, increased only slowly or did not change after treatment with Se and with Se plus EPO. In the group treated with Se plus EPO the element concentration in blood components was higher compared with the group supplemented with Se alone. The weak or absence of response in plasma GSH-Px activity to Se supply indicates that the impaired kidney of uremic HD patients has reduced possibilities to synthesize this enzyme.

Topics: Adolescent; Adult; Aged; Antioxidants; Erythropoietin; Glutathione; Glutathione Peroxidase; Humans; Kidney; Middle Aged; Renal Dialysis; Selenium; Uremia

The efficacy of combined therapy with recombinant human erythropoietin (rhEPO) and vitamin E versus rhEPO alone in the treatment of anemia was examined in children (n = 10, aged 15.2 +/- 3.2 years) on chronic hemodialysis at the restart of rhEPO therapy after a 4-week interval. The results confirmed that rhEPO induced oxidative stress of the red blood cells as observed during the first rhEPO therapy. Vitamin E (15 mg/kg per day per os) was introduced after 2 weeks of rhEPO monotherapy, when the signs of acute oxidative stress appeared. The level of oxidized glutathione (GSSG) increased from 8.9 +/- 3.1 to 26.7 +/- 5.7 nmol/g hemoglobin (Hb) by that time. After 2 weeks of simultaneous vitamin E treatment, there was a significant difference in GSSG values compared with rhEPO monotherapy (10.1 +/- 3.9 vs. 56.7 +/- 15.8 nmol/g Hb, P < 0.001). A considerable decrease was observed in the previously high ratio of GSSG/reduced glutathione (GSH), an indicator of oxidative stress, and the level of carboxyhemoglobin, indicating hemolysis. A significant increase in Hb and hematocrit (P < 0.01) was achieved within 2 weeks of starting the combined therapy, while similar results occurred only at the 8th and 5th weeks without vitamin E. Antioxidant vitamin E supplementation improved the therapeutic effect of rhEPO in patients with chronic renal failure on hemodialysis.

Topics: Adolescent; Antioxidants; Carbon Monoxide; Child; Erythropoietin; Female; Glutathione; Hematocrit; Hemoglobins; Humans; Iron Compounds; Male; Oxidation-Reduction; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia; Vitamin E

Hypothalamic cholinergic neurotransmission plays a major role in the regulation of GH secretion. Pyridostigmine, a cholinesterase inhibitor, is able to decrease hypothalamic somatostatinergic tone and release GH in normal subjects. Blockade of muscarinic receptor with pirenzepine blunts the GH release in several clinical situations. However, little information is available on the role played by central cholinergic pathways in GH regulation in uraemic patients.. We aimed to assess GH responses to GHRH after pretreatment with pyridostigmine and pirenzepine in a group of uraemic patients undergoing peritoneal dialysis (PD). GH responses of the patients treated with recombinant human erythropeitin (rhEPO) were compared to patients without treatment.. We studied 14 male patients on PD and nine control subjects. All subjects underwent three endocrine test in random order after an overnight fast. Each subject received GHRH (100 microg, i.v. in bolus at 0 minutes). Sixty minutes before the injection of GHRH subjects were given oral placebo, pyridostigmine (120 mg), or pirenzepine (100 mg).. Blood samples for GH were collected at -60, 0, 15, 30, 45, 60 and 90 minutes The hormonal secretory responses were studied by a time-averaged (area under the curves, AUC) and time-independent (peak values) analysis.. Baseline GH concentrations were similar in patients and controls. GH responses to placebo plus GHRH were also comparable in patients and controls (peak 26.6 +/- 3.8 vs. 33.2 +/- 4.4 mU/l, AUC 28.2 +/- 3.4 vs. 27.8 +/- 4.6 mU/h/l). Pyridostigmine administration induced a significant potentiation of GH responses to GHRH both in patients (peak 43.2 +/- 5.2 mU/l, AUC 47.6 +/- 6.0 mU/h/l; P < 0.01) and in control subjects (peak 79.2 +/- 8.6 mU/l, AUC 78.0 +/- 9.4 mU/h/l; P < 0.01). However, the increment in GH peak and AUC was significantly (P < 0.05) greater in controls in relation to values found in patients. Pirenzepine administration induced an abolishment of GH release after GHRH stimulation both in PD patients (peak 5.4 +/- 2.6 mU/l, AUC 6.0 +/- 2.4 mU/h/l; P < 0.01) and in healthy controls (peak 3.8 +/- 0.6 mU/l, AUC 4.0 +/- 0.4 mU/h/l; P < 0.05). Responses to pyridostigmine plus GHRH and pirenzepine plus GHRH were similar in patients on chronic therapy with recombinant human erythropeitin and in patients without rhEPO therapy.. These results suggest that the cholinergic regulation of GH release is preserved in uraemic patients on peritoneal dialysis. The significantly lower increase in GH response to GHRH induced by pyridostigmine suggests that cholinergic stimulatory tone is attenuated in patients in relation to control subjects. Long-term therapy with rhEPO seems not to affect GH responses to cholinergic stimulation or blockade.

Topics: Adult; Area Under Curve; Cholinesterase Inhibitors; Erythropoietin; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Male; Muscarinic Antagonists; Peritoneal Dialysis; Pirenzepine; Pyridostigmine Bromide; Recombinant Proteins; Uremia

Iron deficiency constitutes the major cause of erythropoietin hyporesponse in uremic patients receiving erythropoietin therapy; therefore, iron supplementation is necessary for these patients. Recent data suggested that intravenous iron supply is a preferable route for iron supplementation. However, it remains unclear whether a single large dose or multiple small doses are a better way of administering an intravenous iron supply.. To determine the effect of different dosing schedules of intravenous iron therapy on the hematocrit level, we randomly assigned 18 patients to 3 groups. The first group of patients (n = 6) received a single dose of 800 mg intravenous fesin (ferric saccharate). The second group of patients (n = 6) received 400 mg intravenous fesin once weekly for 2 successive weeks. The third group of patients (n = 6) received 120 mg of intravenous fesin for 7 successive hemodialysis sessions. EPO was given at a fixed dose for all individuals in the study period.. The results showed that all 3 groups of patients had a progressive increase in hematocrit (Hct) level following intravenous iron therapy. Serum ferritin levels increased rapidly following iron therapy and then declined gradually in all 3 groups. But no statistical significance could be found among the 3 groups because of the small patient number. Also, no differences were observed in Hct or serum ferritin levels among these 3 groups of patients at all stages.. In this study, we found that a large single dose as well as small multiple doses of parenteral iron therapy had similar effects in correcting the iron deficiency in hemodialysis patients treated with erythropoietin. To save manpower and costs, we recommend the large single dosing schedule.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematocrit; Humans; Infusions, Intravenous; Injections, Intravenous; Iron Deficiencies; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Adult; Aged; Anemia; Biocompatible Materials; Biological Factors; Cardiovascular Diseases; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Hypoxia; Informed Consent; Male; Membranes, Artificial; Middle Aged; Permeability; Polymethyl Methacrylate; Recombinant Proteins; Renal Dialysis; Uremia

Recombinant human erythropoietin (rhEPO) is being successfully used for the treatment of uremic anemia. Short-term studies have proved that correction of anemia with rhEPO therapy is accompanied by several changes in growth hormone (GH) secretion in uremic patients. The present study aimed to assess the influence of long-term rhEPO therapy on baseline and stimulated GH concentrations in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Seven well-nourished and clinically stable CAPD patients were studied. Ten normal subjects were studied as controls. GH responses to direct pituitary stimulation with GH-releasing hormone (GHRH) (100 microg intravenously [i.v.]) and indirect hypothalamic stimulation with insulin-induced hypoglycemia (0.1 U/kg body weight i.v.) and clonidine (0.15 mg/m2 orally), were assessed before and after 3, 6, and 12 months of subcutaneously administered rhEPO therapy. After rhEPO administration, an increase of the hemoglobin concentration was observed in all patients and maintained at about 12 g/dL throughout the study period. rhEPO therapy did not induce any significant change in baseline concentrations of GH and insulin-like growth factor I. Correction of the anemia was accompanied by a clear increase in the area under the curve (AUC) and the area above the baseline (AAB) of GH secretion in response to GHRH stimulation. These changes were statistically significant after 3 and 6 months of therapy, although at 12 months no significant differences in relation to pretreatment values could be observed. rhEPO treatment was associated with a progressive decrement in the GH AUC and AAB in response to hypoglycemic challenge, reaching statistically significant values at months 6 and 12. On the other hand, compared with the control group, GH responses to clonidine were blunted at the start of the study in CAPD patients, and rhEPO therapy was not accompanied by any modification. In conclusion, long-term treatment with rhEPO in CAPD patients is associated with complex and profound effects on somatotrope cell function, characterized by diverse effects on GH responses to stimuli that release GH through different mechanisms. Some of these rhEPO-induced alterations in somatotrope function are dependent on the duration of treatment.

Topics: Adrenergic alpha-Agonists; Adult; Aged; Clonidine; Erythropoietin; Female; Hormones; Human Growth Hormone; Humans; Insulin; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Uremia

Overexpression of glutathione S-transferase (GST; EC 2.5. 1.18) has been documented in the erythrocytes of patients with chronic renal failure, and this event may well be of relevance from a clinical standpoint. In fact, it could serve as a marker of uremic toxicity overall, which can contribute to impair the function and survival of the erythrocytes. However, the biochemical details of this phenomenon are poorly understood.. In this study, we characterized the expression of GST in erythrocytes of 118 uremic patients under different clinical conditions. The mechanisms responsible for the regulation of protein expression and enzyme activity were investigated in light of different dialysis approaches, oxidative stress, uremic toxins, erythrocyte age, and erythropoietin (EPO) supplementation.. Mean GST activity in uremic patients was highly overexpressed with respect to controls, and this phenomenon was exclusively attributable to an increased expression of GST. Overexpression of GST did not appear to be dependent on oxidative stress and was not influenced by vitamin E supplementation. In the same manner, both erythrocyte age and EPO supplementation apparently did not interfere with the GST concentrations, which were the same in controls and patients. Preliminary experiments suggested that high-molecular weight or protein-bound toxins could play some role in the overexpression of GST.. GST expression may be a useful marker for the individual accumulation of uremic toxins as well as of the efficiency of new dialysis strategies in removing them.

Topics: Biomarkers; Blotting, Western; Dialysis Solutions; Erythrocytes; Erythropoietin; Fatty Acids; Female; Glutathione; Glutathione Transferase; Humans; Kinetics; Lipid Peroxidation; Male; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia; Vitamin E

The uremic patient on regular hemodialysis (RHD) is subjected to a wide range of immune modulators including the uremic state per se, multiple transfusions and exposure to bioincompatible materials and endotoxins. Erythropoietin (EPO) therapy may raise concern about its potential influence on this complex scenario. To envisage this issue, 15 adequately selected patients, stable on RHD, were randomly assigned in a 2:1 ratio into EPO and placebo groups. After initial assessment and determination of baseline values, they received, in a double-blind manner, either EPO or normal saline as an intravenous bolus immediately after termination of dialysis for 30 successive sessions. Thirty minutes later, following sessions 1, 10, 20, and 30, samples were obtained for determination of blood counts, red cell indices, peripheral lymphocyte counts (PLC), CD4/CD8 ratios, blood EPO levels, and serum concentrations of interleukins (IL) IL-2r, IL-3, and IL-6, tumor necrosis factor (TNFs and TNFalpha), and neopterin (NPT). Blood EPO levels displayed the predicted rise in the EPO group, which correlated with partial improvement of red cell parameters. The mean total leukocyte count and PLCs was significantly increased in the EPO group (p < 0.05) but not in the placebo group. CD4/CD8 ratios were not significantly changed in either group. The serum concentrations of IL-2r, IL-3, and NPT remained fairly stable while that of IL-6 was widely variable in both study groups. The mean serum concentrations of TNF and particularly TNFalpha showed a steady and statistically significant increment in the EPO group from 6 to 41 pg/ml (p < 0.05) and 93 to 128 pg/ml (p < 0.03), respectively. No significant change was noticed in the control group. It is concluded that intravenous administration of EPO under the conditions of this study may have an immune stimulating effect. This is shown by the release of TNFs, which in turn may be responsible, through different potential mechanisms, for the increase in the mean peripheral neutrophil count and the blunting of erythroid responsiveness to EPO therapy.

Topics: Adjuvants, Immunologic; Adult; Blood Cell Count; CD4-CD8 Ratio; Double-Blind Method; Erythropoietin; Female; Hematocrit; Humans; Injections, Intravenous; Interleukins; Male; Middle Aged; Neopterin; Prospective Studies; Recombinant Proteins; T-Lymphocytes; Tumor Necrosis Factor-alpha; Uremia

Topics: Aluminum; Erythropoietin; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Recombinant Proteins; Uremia

Recombinant human erythropoietin improves platelet function in uremia through the correction of anemia, but this effect can be seen also before the hematocrit rise. We studied 12 hemodialyzed patients (seven men, five women) who received recombinant human erythropoietin (40 IU kg(-1)i.v., three times weekly) and were evaluated before treatment and after three doses; 24 control subjects were used. Platelet aggregation induced by adenosine 5'-diphosphate (ADP), epinephrine, collagen, arachidonic acid, and ristocetin, and reticulated platelets determined by flow cytometry after staining with thiazole orange were measured. Platelet aggregation induced by all the agonists were impaired in uremic patients (P < 0.01), but ADP and ristocetin-induced aggregations improved after treatment (P < 0.01). Hemodialyzed patients had less reticulated platelets than controls (P < 0.01). Reticulated platelets increased after three doses of treatment (P < 0.01). In conclusion, improvement of platelet function at early stages of recombinant human erythropoietin treatment may be attributed to the increase in young platelets detected as reticulated platelets.

Topics: Adenosine Diphosphate; Adult; Age Factors; Aged; Blood Platelets; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Platelet Count; Recombinant Proteins; RNA; Time Factors; Uremia

In a prospective study, 40 maintenance hemodialysis patients, randomized in two equal groups, were treated with recombinant human erythropoietin (rHuEPO) for their renal anemia, for a period of 2 years. One group was treated for 2 years, while the other was untreated control during the first year, but received rHuEPO during the second year of the study. Anemia was corrected in all treated patients and hematocrit maintained between 30 and 35 vol% by low-dose subcutaneous treatment with Recormon (Boehringer Mannheim GmbH, Germany), according to the study protocol. Bone marrow biopsy (BMB), from the posterior iliac crest, was taken by the method of Jamshidi from 32 patients. Fourteen patients from the control group were biopsied twice: once at baseline and the second time at 12 months of treatment, while 15 patients from the other group were biopsied only once, at 24 months of rHuEPO treatment. The biopsies were embedded in wax and in epoxy resin, and after staining for light and electron microscopy, they were semiquantitatively examined for several parameters: cellularity, myeloid:erythroid (M:E) ratio, megakaryocytes, fatty tissue, megaloblasts, and marrow iron. Cellularity of the bone marrow increased significantly at 12 months of treatment and it remained so at 24 months. M:E ratio was significantly reduced indicating expansion of the erythroid pool, both at 12 and 24 months of therapy. The number of megakaryocytes in the bone marrow increased significantly at 12 months and remained high at 24 months of treatment, while fatty tissue was significantly reduced at 12 and 24 months compared to the baseline values. There was no significant change in the percentage of megaloblasts in the bone marrow. Hemosiderin was reduced after treatment indicating mobilization of the bone marrow iron stores upon treatment with rHuEPO. We concluded that rHuEPO had a beneficial long-term effect on bone marrow.

Topics: Anemia; Biopsy; Bone Marrow; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Growing evidence suggests that it is possible to seroconvert chronic renal failure patients who are absolute non-responders to hepatitis B vaccine by means of either additional booster vaccine doses or associated IL-2 administration or both. We have studied the possibilities of hepatitis B seroconversion by revaccination and its dependence on vaccine dose, and the effects of a concurrent low-dose rHuIL-2 regime.. Forty known absolute non-responders with chronic renal failure were entered into a complete revaccination protocol. Patients were randomly assigned to two dosage groups of either 20 or 40 micrograms hepatitis B vaccine administered at 0, 1, 2 and 6 months. Further randomly selected patients from each dosage group were given 500,000 U of rHuIL-2 in the same deltoid area 4 h after vaccine administration.. Sixty-seven per cent of patients revaccinated with 40 micrograms attained antibody protecting levels compared to only 20% of those receiving doses of 20 micrograms (P < 0.025). When compared with initial values, the ThCD4/CD25 cell count was significantly reduced immediately after HuR-IL2 administration (P < 0.003) and significantly increased 1 month after the last dose was given (P < 0.0003). A definite rHuIL-2 effect on HBV antibody synthesis could not be demonstrated, nor was erythropoietin found to enhance seroconversion.. From these results we suggest that more intense and frequent antigenic stimulation as obtained by revaccination using four doses of 40 micrograms may effectively reduce the pool of hepatitis B vaccine nonresponders in chronic renal failure patients.

Topics: Clinical Protocols; Erythropoietin; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Vaccines; Humans; Immune Tolerance; Immunization, Secondary; Interleukin-2; Recombinant Proteins; Uremia; Vaccines, Synthetic

Hearing loss is a common finding in patients with end-stage renal failure. Uremic toxins, ototoxins, and axonal uremic neuropathy appear to be likely pathogenic factors. We analyzed whether an improvement in hearing capacity can be achieved with an improvement of anemia by erythropoietin (EPO) administration. Fifty patients on long-term hemodialysis in a single center were examined audiologically by otoscopy, tympanometry, pure tone audiometry, and the short increment sensitivity index. Twenty-five patients were treated with EPO in a dose of 120 U/kg per week over a period of 5 to 8 months, and the remaining 25 patients were not treated with EPO (controls). Both groups were reexamined audiologically after the study period, and the results were compared. In the group treated with EPO, the hemoglobin level increased from 7 +/- 0.9 to 11 +/- 0.8 g/dL, as against the control group, whose hemoglobin increased from 7.1 +/- 0.9 to 8 +/- g/dL. The audiologic tests were repeated at the end of the study period, and a significant improvement of hearing was found in the patients treated with EPO as compared with the control group (p < .001). Our study suggests that improvement of anemia in patients on long-term hemodialysis by administration of EPO is associated with an improvement in hearing capacity in a significant number of patients. Thus, anemia seems to be an important factor responsible for hearing disorders in patients with end-stage renal failure. Studies with larger numbers of patients are required to confirm this observation.

Topics: Anemia; Deafness; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

An important role in the formation of hemostasis defects in uremic patients is attributed to platelet dysfunction. An essential role in platelet structure and function is played by membrane phospholipids (PL). They are asymmetrically distributed within the platelet membrane: outer surface is composed mainly of sphingomyelin (Sph) and phosphatidylcholine (PC). During platelet activation a translocation of phosphatidylserine (PS) and phosphatidylethanolamine (PE) from inner to outer membrane surface is observed. Phosphatidylinositol (PI) is not translocated. Lipid abnormalities are common in uremic patients. According to some authors erythropoietin (EPO) has been reported to alter lipid metabolism. In our recent works a positive influence of EPO on platelet PL composition in uremic patients has been indicated. The aim of this study was the assessment of the EPO influence (applied 4000 U per week) on platelet membrane PL distribution in chronically hemodialyzed patients. The PL distribution was determined using nonpenetrating tracer (TNBS) by Vale method, and using high purified phospholipases hydrolysis according to Chap method. Our results indicate that during EPO therapy the PS, PE, Sph and PC exposition at the outer surface of platelet membrane (in patients hemodialyzed without EPO widely disturbed compared with healthy controls) approaches to normal values. These results confirm our recent observations that EPO profoundly interferes with lipid metabolism. The smaller PS exposition at the outer platelet surface during EPO treatment suggests less platelet activation, and might partially explains the positive EPO influence on platelet hemostasis.

Topics: Adult; Blood Platelets; Cell Membrane; Erythropoietin; Female; Humans; Male; Middle Aged; Phospholipids; Platelet Activation; Recombinant Proteins; Renal Dialysis; Uremia

The influence of angiotensin-converting enzyme inhibitors (ACEIs) on recombinant human erythropoietin (rhEPO) maintenance doses in hemodialysis patients was studied. One hundred and eight chronic hemodialysis patients (55 males and 53 females, mean age 61.2+/-12.6 years) were investigated. The rhEPO maintenance doses in the ACEI-treated group (n = 49) were 101.7+/-51.7 U/kg/week and in the nontreated group (n = 59) 79.2+/-37.8 U/kg/week (p < 0.05). No difference was observed in hematocrit between the ACEI-treated and nontreated groups. In stepwise regression analysis, the parameters associated with increased rhEPO maintenance doses were female gender, ACEI administration, low total iron binding capacity, and low serum free carnitine levels. In conclusion, ACEI administration might reduce the response to rhEPO. In hemodialysis patients who need high-dose rhEPO to maintain the target hematocrit in the absence of iron deficiency, hyperparathyroidism, infection, malignancy, malnutrition, and aluminum toxicity, ACEI administration should be considered.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Dialysis; Sex Characteristics; Uremia

Long-term therapy with recombinant human erythropoietin (rhEPO) in uremic male patients undergoing hemodialysis has been followed by an increase in plasma levels of testosterone and a decrease in baseline levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The aim of the present study was to assess the effect of acutely administered rhEPO on FSH and LH responses to gonadotropin-releasing hormone (GnRH) in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Sixteen clinically stable male patients (age, mean+/-SEM, 45.3+/-3.9 years) with chronic renal insufficiency and 12 healthy volunteers with a normal renal function, matched for age and body mass index, were studied. All patients were on CAPD therapy for at least 3 months, and none of them received rhEPO therapy. Patients were moderately anemic (hemoglobin 11.0+/-0.3 g/dl) and showed testosterone levels significantly lower than those found in control subjects (3.47+/-0.37 vs. 6.91+/-0.49 ng/ml, p < 0.001). Each subject was tested with GnRH (100 microg i.v. as bolus) and with GnRH plus rhEPO (40 U/kg at a constant infusion rate for 30 min, starting 15 min before GnRH injection) on different days. Blood samples for FSH and LH were obtained between -30 and 120 min. In uremic patients the baseline FSH levels were higher than those found in control subjects (18.88+/-5.41 vs. 6.41+/-1.10 mU/ml, p < 0.05). After GnRH administration FSH values reached a maximum of 25.50+/-6.19 mU/ml in patients and of 12.50+/-2.02 mU/ml in controls (p < 0.05). rhEPO infusion produced a significant (p < 0.01) decrease in the area above the baseline value of FSH in uremic patients, with no other change in FSH responses to GnRH both in patients and controls. Baseline LH concentrations were significantly higher in patients than in controls (15.56+/-3.41 vs. 2.58+/-0.36 mU/ml, p < 0.001). LH peak and area under the curve of LH secretion after GnRH were significantly higher in patients than in controls (45.25+/-6.28 vs. 26.83+/-4.62 mU/ml, p < 0.05, and 77.02+/-11.30 vs. 34.40+/-5.22 mU x h/ml, p < 0.005, respectively). When GnRH was injected during the rhEPO infusion, a significant (p < 0.02) reduction in LH concentrations at 60, 90, and 120 min was found in uremic patients. Accordingly, the LH area under the curve was significantly reduced in patients (65.99+/-11.44 mU x h/ml, p < 0.05). rhEPO had no effect on GnRH-induced LH release in control subjects. These results sugges

Topics: Adult; Erythropoietin; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Luteinizing Hormone; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Uremia

Topics: Adult; Anemia; Endothelins; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Urea can dissociate in vivo to form isocyanic acid which can react with hemoglobin to form carbamylated hemoglobin. Previous work has shown that formation of carbamylated hemoglobin depends upon both the severity and the duration of renal failure. To determine whether carbamylated hemoglobin can be used as an assessment of the adequacy of hemodialysis treatment, we prospectively studied 55 stable patients who regularly attended our hospital dialysis program. Carbamylated hemoglobin was greater in those patients with a Kt/V of < or = 1.1 compared to those with a Kt/V of > 1.1 (120 +/- 8 micrograms VH/gHb versus 99 +/- 7, P < 0.01), and there was a negative correlation with Kt/V (r = -0.37, P = 0.007). There were positive correlations between carbamylated hemoglobin and the time-averaged urea concentration (r = 0.4, P = 0.004), and a negative correlation with the urea reduction ratio (r = -0.37, P = 0.01). Carbamylated hemoglobin may therefore be a useful marker of the degree of uremia, just as glycosylated hemoglobin is used in the assessment of patients with diabetes mellitus.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers; Carbamates; Diabetes Mellitus; Erythropoietin; Female; Hemoglobin A; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Sex Factors; Uremia

Correction of anemia with recombinant human erythropoietin (rhEPO) in patients with end-stage renal disease has been associated with improvement of several abnormalities in hypothalamo-hypophyseal functions. The aim of the present work was to evaluate the growth hormone (GH) responses to GH-releasing hormone (GHRH) and clonidine stimulation, as well as the baseline concentrations of insulin-like growth factor I(IGF-I), before and after the correction of anemia with rhEPO in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Nine clinically stable patients (1 male, 8 female; mean age 55.4 years; mean duration of CAPD 14.1 months) were studied. Twelve normal volunteers were studied as controls. GHRH and clonidine stimulation tests were performed prior to starting rhEPO and again after partial correction of anemia with rhEPO therapy (60-130 U/kg/week, s.c., for 12 weeks). Blood samples for GH were collected during 2 h after GHRH (100 micrograms i.v. in bolus) or clonidine (0.15 mg/m2, p.o.) administration. In basal plasma samples IGF-I concentrations were also measured. Mean (+/- SEM) blood hemoglobin concentration rose from 5.32 +/- 0.25 to 7.22 +/- 0.25 mmol/l (p < 0.001) after rhEPO treatment. GH responses to GHRH were characterized by marked differences in single patients when compared with the control group. However, the GH peak and the area under the secretory curves (AUC) of GH responses in CAPD patients (9.89 +/- 4.01 micrograms/l and 15.06 +/- 6.02 micrograms.h/l, respectively) did not differ from those obtained in control subjects (14.58 +/- 3.25 microgram/l and 16.94 +/- 4.31 microgram.h/l, respectively). The study after correction of anemia showed an evident potentiation of GH values that reached statistically significant values at 60 and 90 min. GH AUC after rhEPO therapy rose to 25.61 +/- 9.25 micrograms.h/l (p = 0.01). In control subjects, clonidine administration was followed by a GH release that reached a maximum at 90 min (7.67 +/- 2.24 micrograms/l). However, CAPD patients exhibited a blunted response to clonidine both before (2.00 +/- 0.78 microgram/l) and after (2.78 +/- 0.76 microgram/l, NS) correction of the anemia with rhEPO. On the other hand, IGF-I concentrations after rhEPO therapy (32.05 +/- 5.52 nmol/l) were not significantly different from those found prior to starting therapy (38.13 +/- 8.44 nmol/l). In conclusion, these results suggest that correction of the anemia with rhEPO therapy potent

Topics: Adrenergic alpha-Agonists; Adult; Aged; Anemia; Clonidine; Erythropoietin; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Stimulation, Chemical; Uremia

This study aimed to assess the influence of short-term therapy with recombinant human erythropoietin (rhEPO) on selected parameters of humoral and cell mediated immunity in haemodialyzed uraemic patients (HDP). In 12 HDP before, and after 1 and 3 months of rhEPO therapy the following parameters were assessed: nitroblue tetrazolium (NBT) test, NBT test after latex stimulation, number of B, T and CD4 and CD4- and CD8-positive T lymphocytes, serum concentrations of IgG, IgA and IgM. The number of granulocytes with a positive NBT test was significantly higher after 3 months of rhEPO therapy. The number of granulocytes with a positive NBT test after latex stimulation increase both after 1 and 3 months of rhEPO therapy but significantly only after 3 months of treatment. The number of CD4-positive T lymphocytes increased significantly after 3 months of rhEPO therapy, while the number of CD8-positive lymphocytes decreased significantly after 1 month of therapy. The CD4/CD8 ratio increased significantly after 3 months of rhEPO therapy. Serum IgA concentration increased significantly after 1 and 3 months, while serum IgG level only after 3 months of rhEPO therapy. From the results obtained in this study it follows that rhEPO therapy exerts a positive effect on function of both T and B lymphocytes in haemodialyzed uraemic patients.

Topics: Adult; Antibody Formation; Blood Cell Count; Erythropoietin; Female; Humans; Immunity, Cellular; Immunoglobulins; Lymphocyte Count; Male; Recombinant Proteins; Renal Dialysis; Rosette Formation; Uremia

To investigate the effects of erythropoietin (rHuEPO) therapy supplemented or not with iron on hemolysis in hemodialysed patients (HD) we evaluated lipoperoxidation (LPO) by assaying (i) the red blood cell (RBC) antioxidant enzymatic system including superoxide dismutase (SOD), glutathione peroxidase, and catalase (Cat), (ii) RBC polyunsaturated fatty acids (PUFA) and (iii) malondialdehyde (MDA). Group 1 included 12 HD patients, group 2 had 7 HD patients with iron supplementation, group 3 comprised 12 HD patients with rHuEPO therapy and group 4 included 9 HD patients with both iron and rHuEPO therapies. No LPO was found in group 1 as regards MDA and PUFA levels. However, SOD and Cat activities were significantly elevated as compared to controls (p < 0.001). In the second group, a significant decrease in PUFA percentage was observed, particularly in 20:4(n-6) and 22:4(n-6) (the main ones involved in LPO) as compared to the other groups, whereas total MDA level was higher than that of the other groups. Similarly a decreased SOD activity was observed as compared to group 1 (p < 0.001), indicating its inactivation subsequent to an hyperproduction of reactive oxygen species through iron injection. In groups 3 and 4 no change was observed in MDA levels or PUFA percentages indicating no LPO. However, marked differences were observed in the enzymatic defense system. Particularly in group 3, SOD and Cat activities decreased when compared to group 1 (p < 0.001) whereas the association of erythropoietin and iron (group 4) increased the three enzymatic activities (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Catalase; Erythrocytes; Erythropoietin; Fatty Acids, Unsaturated; Female; Glutathione Peroxidase; Humans; Iron; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Renal Dialysis; Superoxide Dismutase; Uremia

Six chronic hemodialysis patients suffering from iron overload (serum ferritin ranged between 2053-15704 mu g/L) were treated with human recombinant erythropoietin (EPO) alone for eighteen months. An initial rapid decrease of serum ferritin was observed in all six patients when the loading dose of EPO was given. Three patients (Cases 4, 5, 6) who suffered from chronic blood loss maintained a continuous decline of serum ferritin in the subsequent stage of maintenance dose EPO therapy, however, the decrease of serum ferritin became sluggish under a maintenance dose in the other three patients (Cases 1, 2 and 3). The serum ferritin eventually decreased to a satisfactory level (975-1761 mu g/L) in Cases 4, 5 and 6, whereas it remained high (4232-8196 mu g/L) in Cases 1, 2, and 3 who had higher basal levels of serum ferritin (5641-15704 mu g/L) and a plateau of response under a maintenance dose of EPO. These three patients were then treated with EPO and phlebotomy. Their serum ferritin decreased quickly from 6752 +/- 1264 mu g/L to 2454 +/- 482 mu g/L after six months of phlebotomy therapy; it was a dramatic improvement in contrast to the stagnant response under a maintenance dose of EPO alone. Our experience indicates that EPO therapy alone has its limitations in treating severe iron overload. Although there is an initial rapid decrease of serum ferritin during the period of the loading dose, the response might become stagnant during the period of maintenance dose. Phlebotomy effectively eliminated the excessive iron stores in these refractory cases. Therefore, we suggest that phlebotomy be considered in severe iron overload if a stagnant response is observed under a maintenance dose EPO therapy.

Topics: Adult; Combined Modality Therapy; Erythropoietin; Female; Hemosiderosis; Humans; Male; Middle Aged; Phlebotomy; Prospective Studies; Recombinant Proteins; Uremia

In a retrospective study, antiplatelet therapy has been shown to be associated with a decreased incidence of erythropoietin-induced hypertension. In order to ascertain the role of antiplatelet drugs in the haemodynamic response to the correction of anaemia by rHuEpo, 18 patients on chronic haemodialysis who started rHuEpo therapy were prospectively studied.. The subjects were randomly assigned to receive or not, one of the following antiplatelet drugs: ditazole (3 patients), ticlopidine (3 patients) or aspirin plus dipyridamole (3 patients). Cardiac index (CI) by echo-Doppler, total peripheral resistance (TPR) and mean arterial pressure (MAP) were determined at baseline 10 and 20 weeks following the initiation of rHuEpo therapy. rHuEpo therapy was administered subcutaneously at the same dose (40 U/kg thrice weekly) during the first 10 weeks. Ten uraemic patients on haemodialysis who had never received rHuEpo therapy served as the control group.. One patient in the group without antiplatelet drugs discontinued the study due to the development of severe hypertension after 12 weeks on rHuEpo therapy. There were no significant differences in the haemodynamic parameters at baseline. At 10 weeks, MAP was higher in patients without than with antiplatelet drugs or controls untreated with rHuEpo (128.5 +/- 28 versus 100.6 +/- 13.5 versus 98.7 +/- 14 mmHg respectively, P = 0.0047), TPR was also higher in patients without antiplatelet drugs than in the 2 other groups (1919 +/- 433 versus 1576 +/- 359 versus 1418 +/- 324 din.seg.cm-5m2 respectively, P = 0.0231), but CI did not differ among the three groups. At 20 weeks, MAP was still higher in patients without antiplatelet drugs than in patients with antiplatelet drugs or controls not on rHuEpo therapy respectively (112.9 +/- 24.6 versus 91.0 +/- 9.0 versus 101.7 +/- 14.1 mmHg respectively, P = 0.075), but at this stage TPR and Cl did not differ among the three groups.. These data reinforce the previous observation that antiplatelet therapy may prevent the development of rHuEpo-induced hypertension.

Topics: Adult; Aged; Anemia; Aspirin; Dipyridamole; Erythropoietin; Female; Hemodynamics; Humans; Male; Middle Aged; Oxazoles; Platelet Aggregation Inhibitors; Prospective Studies; Recombinant Proteins; Renal Dialysis; Ticlopidine; Time Factors; Uremia

Psychometric performance was studied in 17 patients maintained on CAPD. Nine patients treated with rHuEpo performed a battery of psychometric tests before treatment (haemoglobin mean (SD) 6.8 (0.8) g/dl) and after partial correction of anaemia (haemoglobin 9.0 (1.0) g/dl). The same battery of psychometric tests was administered to eight patients (haemoglobin 7.7 (0.7) g/dl), matched with the treatment group for age, duration of dialysis and social class, who did not receive rHuEpo. The National Adult Reading Test was used in all patients to estimate the premorbid IQ (the peak cognitive level attained before any cognitive deterioration). In the rHuEpo-treated group current IQ, measured by a short form of the Wechsler Adult Intelligence Scale--Revised, improved by a mean of 7.2 points (P < 0.01) and approached estimated premorbid levels, while in the control group an improvement by 0.3 points was not significant. Concentration and speed of information processing were assessed by the Paced Auditory Serial Addition Task and also improved in the treatment group (P < 0.05). Memory, assessed by the Rey Auditory Verbal Learning Test, tended to improve in the treatment group with amelioration of anaemia, although only the improvement in delayed recall was significant. No overall change was seen in either group in the time taken to complete the Trail Making Test (part A). These results are consistent with our earlier findings in haemodialysis patients, indicating that anaemia makes a reversible contribution to uraemic cognitive dysfunction.

Topics: Adult; Aged; Anemia; Cognition; Erythropoietin; Female; Hemoglobins; Humans; Intelligence; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Psychometrics; Recombinant Proteins; Uremia

The study aimed to assess the influence of long-term rhuEPO treatment on secretion of pancreatic hormones (insulin, glucagon). A total of 27 haemodialyzed and 9 healthy subjects were examined. Nine patients with uraemic anaemia were treated with rhuEPO for 12 months (EPO group) while another nine patients did not receive rhu-EPO (non-EPO group), but were monitored biochemically and clinically as patients of the EPO group. The third group (HD) comprised nine haemodialyzed patients with a haematocrit value of > 30%, without rhu-EPO therapy. In all subjects plasma levels of glucose, insulin (IRI) and glucagon (Glu) were estimated before and after administration of the test meal. Patients of the EPO and non-EPO group were examined before and after 6 and 12 months of rhu-EPO treatment (EPO group) or clinical monitoring (non-EPO group) respectively, while only one test was performed in patients of the HD group and healthy subjects. During the observation period fasting glicaemia did not change. Six months of rhu-EPO therapy was followed by an increase of fasting insulinaemia and decrease of basal plasma level of glucagon. At that time point rhu-EPO therapy also increased the response of IRI and Glu to the test meal and the insulin/glucose index. After 12 months of rhu-EPO therapy basal insulinaemia and insulin/glucose index returned to the pretreatment value while plasma level of glucagon and the response to the test meal were lower than pretreatment one. Our results suggest that rhu-EPO treatment exerts a profound effect on carbohydrate metabolism and secretion of IRI. Glu, which seems to be dependent upon duration of rhu-EPO therapy and not only, or exclusively to improvement of the haematological status.

Topics: Adult; Blood Glucose; Carbohydrate Metabolism; Drug Administration Schedule; Erythropoietin; Humans; Insulin; Kidney Failure, Chronic; Middle Aged; Pancreatic Hormones; Recombinant Proteins; Renal Dialysis; Uremia

rHuEpo and iron therapy corrects renal anaemia. However, dosage, route of administration, and monitoring of iron and rHuEpo therapy in uraemic patients remains controversial.. Therefore a 22-month i.v. iron substitution trial, subdivided into four study periods, was initiated in 64 iron-depleted chronic haemodialysis (HD) patients receiving i.v. rHuEpo therapy. Within the first period (6 months) patients were treated with high-dose iron (100 mg at the end of HD treatment, mean cumulative i.v. iron saccharate dosage was 2538 +/- 810 mg per patient) in order to replete the iron stores. During the 2nd period (6 months) the available iron pool was maintained with low-dose iron by administration of 10, 20, or 40 mg iron at each HD, depending on haemoglobin, serum ferritin and transferrin saturation levels. During the 3rd period (4 months), the iron-replete patients were randomized to i.v. or s.c. route of rHuEpo administration. During the 4th period (3 months) iron substitution was omitted to exclude severe iron overload.. In the first study period, high-dose iron therapy dramatically reduced the weekly rHuEpo requirement by 70% of the initial dose (from 217 +/- 179 to 62.6 +/- 70.2 U/kg/week). In the 2nd period iron storage pools were easily maintained. Serum ferritin and transferrin saturation levels remained stable during this study period. Randomization for thrice-weekly i.v. or s.c. administration of rHuEpo in the 3rd study period revealed comparable efficacy for both administration routes in iron-replete patients. In well-nourished patients (serum albumin > 40 g/l) without hyperparathyroidism (parathyroid hormone levels < 100 pg/ml), 50-60 U/kg/week rHuEpo were required in contrast to > 100 U/kg/week in patients with hyperparathyroidism. In the 4th study period, withdrawal of iron administration led to a rapid decrease of serum ferritin and transferrin saturation levels, indicating the absence of severe iron overload.. Long-term thrice-weekly i.v. low-dose iron therapy (10-20 mg per HD treatment) proved to be a very effective, economical and safe treatment schedule for iron-replete HD patients. Intravenous and s.c. rHuEpo therapy was equally efficacious in iron-replete, well-nourished patients. HD patients with increased parathyroid hormone levels require significantly more rHuEpo than HD patients with parathyroid hormone levels values < 100 pg/ml).

Topics: Drug Administration Routes; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Male; Middle Aged; Parathyroid Hormone; Prospective Studies; Serum Albumin; Transferrin; Uremia

Topics: Acetates; Analysis of Variance; Anemia; Calcium; Calcium Carbonate; Drug Administration Routes; Erythropoietin; Female; Follow-Up Studies; Humans; Hyperparathyroidism, Secondary; Male; Parathyroid Hormone; Prospective Studies; Renal Dialysis; Uremia

Ten anemic hemodialysis patients were treated for 6-14 months with human recombinant erythropoietin (EPO). The mean hemoglobin level significantly increased by 42%. Pretreatment skeletal muscle heat production rate at rest, as determined by direct microcalorimetry, was lower than normal (p < 0.03), indicating decreased metabolic activity. ATP levels in muscle were inversely correlated (rs = -0.66, p < 0.05) with the heat production values. The latter significantly increased by about 40% and were almost normalized by the therapy, whereas a decline in the mean ATP level was seen, from 14.8 to 13.2 mumol g-1 of muscle (p = 0.06). We hypothesize that the lowered ATP concentration in muscle after treatment might have been due to an enhanced ATP consumption in parallel with improved muscle strength. Alternatively, since acidosis prior to treatment might have altered the equilibrium state of the creatine kinase reaction towards ATP production, it is possible that the improved oxygenation after EPO had increased pH in the muscle and catalyzed the transfer of phosphate from ATP to PCr. It is concluded that EPO treatment can almost normalize the decreased muscle metabolic rate in hemodialysis patients, and that the anemia per se seems to be an important cause of the deranged metabolism in striated muscle.

Topics: Adenosine Triphosphate; Adult; Aged; Anemia; Calorimetry; Energy Metabolism; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Muscles; Recombinant Proteins; Renal Dialysis; Uremia

Anemia of chronic renal failure is associated with a reduced affinity of hemoglobin for oxygen (Hb-O2 affinity). It has been reported that the correction of renal anemia by recombinant human erythropoietin (rhuEPO) treatment could be associated paradoxically with a further decrease in Hb-O2 affinity. We investigated changes in the compensatory mechanisms of chronic renal anemia during 25 weeks of rhuEPO treatment, in 19 chronic hemodialyzed (HD) patients. There was no significant variation of mean standard P50 (P50std). Average 2,3-diphosphoglycerate (DPG) increased after 13 weeks and remained stable. The large interindividual variations prompted us to study delta P50std and delta Hb. We demonstrated a negative correlation between delta P50std and delta Hb. Thus, P50std increased in patients who did not immediately correct their anemia and decreased in patients whose Hb values rose. These data showed that the major factor influencing variations of Hb-O2 affinity in chronic HD patients treated by rhuEPO is the variation of Hb concentrations. In our study, it was demonstrated that the most important rise in P50std and 2,3-DPG occurred in patients who were late responders to rhuEPO.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Hydrogen-Ion Concentration; Kidney Failure, Chronic; Male; Middle Aged; Oxygen; Recombinant Proteins; Uremia

The oxidative injury to erythrocytes, red blood cell (RBC) rigidity and splenic hemolysis was assayed in 17 chronically hemodialyzed patients before and during recombinant erythropoietin (EPO) treatment. When a stable hematocrit between 30 and 35% had been established for at least 4 months, a statistically significant increase in RBC volume, hemoglobin concentration, hematocrit, reticulocyte count, and several RBC enzymes (2,3-diphosphoglycerate, glucose 6-phosphate dehydrogenase, pyruvate kinase, hexokinase) was noted. This indicated significant RBC rejuvenation under the influence of EPO. However, no significant improvement in the RBC oxidative sensitivity, RBC deformability, splenic RBC volume, slow mixing splenic RBC volume, and the intrasplenic RBC transit time could be disclosed. These data confirm the existence of an extra-erythrocytic factor in uremic plasma, which is partly responsible for a reduced RBC life span in hemodialysis patients despite EPO treatment.

Topics: Adult; Aged; Anemia; Erythrocyte Aging; Erythrocyte Deformability; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidation-Reduction; Reactive Oxygen Species; Renal Dialysis; Sensitivity and Specificity; Spleen; Uremia

We investigated subpopulations of T lymphocytes, NK cell number and cytotoxic activity in 14 chronic uremic patients on regular hemodialysis treatment. We observed a significantly decreased absolute lymphocyte number and percentage of CD3 cells. Relative numbers of CD16 cells were significantly elevated, but NK cell cytotoxic activity was within a normal range. Nine patients with chronic renal anemia on maintenance hemodialysis were enrolled in rHu-EPO treatment trial. The treatment was continued till the hematocrit level reached 30%. Each of the patients had corrected anemia and well-being. After 12 weeks of the treatment we observed in these patients decreases in CD3, CD4, CD8 and CD16 cell numbers and elevation of CD4/CD8 ratio. Cytotoxic activity of NK cells did not change significantly. Presented results indicate that chronic hemodialysis patients have significantly diminished lymphocyte number. rHu EPO treatment affects the T lymphocyte subsets inducing a deep decrease of CD8 and CD16 cell percentage leading to normalisation of the CD4/CD8 ratio.

Topics: Adolescent; Adult; Antigens, Differentiation, T-Lymphocyte; Cytotoxicity, Immunologic; Erythropoietin; Female; Humans; Killer Cells, Natural; Leukocyte Count; Leukopenia; Male; Renal Dialysis; T-Lymphocyte Subsets; Uremia

The erythropoietic response to graded doses of recombinant human erythropoietin (epoetin alfa) was assessed in 24 hemodialysis patients by quantitative ferrokinetic studies, and measurement of the reticulocyte count and plasma levels of transferrin receptor protein. These responses were compared to those of 22 normal subjects. Epoetin alfa was given intravenously at 15, 50 or 150 U/kg every other day for four injections. Three patients with chronic renal failure were restudied after renal function was restored following renal transplantation. The results of these three different measurements of erythroid function showed that the acute response to recombinant human erythropoietin was similar in normal subjects and patients with renal failure. We conclude that chronic uremia does not alter the responsiveness to erythropoietin in vivo.

Topics: Anemia; Erythrocyte Count; Erythropoiesis; Erythropoietin; Humans; Iron; Receptors, Transferrin; Renal Dialysis; Reticulocytes; Uremia

We studied the significance of free erythrocyte protoporphyrin (FEP) in relation to iron status, aluminum levels and anemia in uremic patients on chronic dialysis. All but 1 patient showed high FEP values closely related to the degree of anemia. Increased FEP levels are due to a defective heme synthesis, not related to iron deficiency or aluminum overload. Treatment of anemia with recombinant human erythropoietin reduced FEP values. We therefore hypothesize that recombinant human erythropoietin ameliorates an enzymatic defect in heme synthesis.

Topics: Aluminum; Anemia; Erythrocytes; Erythropoietin; Female; Ferritins; Humans; Male; Middle Aged; Protoporphyrins; Recombinant Proteins; Renal Dialysis; Uremia

The pathophysiologic aspects of pruritus in patients with chronic renal insufficiency are poorly understood, and there is no universally effective treatment. The improvement of pruritus in several patients receiving erythropoietin therapy raised the possibility that erythropoietin affects uremic pruritus directly.. We undertook a 10-week placebo-controlled, double-blind, crossover study in a group of patients receiving hemodialysis who had severe pruritus, to investigate the effects of recombinant human erythropoietin on their pruritus and plasma histamine levels. Twenty patients with uremia, of whom 10 had severe pruritus and 10 did not, received erythropoietin (36 units per kilogram of body weight three times weekly) and placebo in random order, each for five weeks. The severity of pruritus was scored weekly, and plasma histamine levels were measured at the beginning and end of each five-week period.. Eight of the 10 patients with pruritus had marked reductions in their pruritus scores during erythropoietin therapy. The mean (+/- SE) pruritus score decreased from 25 +/- 3 to 6 +/- 1 in these patients. The pruritus returned within one week after the discontinuation of therapy. The improvement was not related to the change in hemoglobin level. These eight patients were successfully treated again with low doses of erythropoietin (18 units per kilogram three times weekly), and the effect has persisted for six months. The patients with pruritus had elevated plasma histamine concentrations (20.7 +/- 2.7 nmol per liter), as compared with the patients without pruritus (4.2 +/- 0.6 nmol per liter; P less than 0.001) and normal subjects (2.1 +/- 0.2 nmol per liter; P less than 0.001). Therapy with erythropoietin induced a decrease in plasma histamine concentrations in both groups of patients with uremia, and recurrences of pruritus after the discontinuation of erythropoietin were accompanied by increases in plasma histamine concentrations.. Erythropoietin therapy lowers plasma histamine concentrations in patients with uremia and can result in marked improvement of pruritus.

Topics: Double-Blind Method; Erythropoietin; Female; Histamine; Humans; Male; Middle Aged; Pruritus; Recombinant Proteins; Renal Dialysis; Uremia

Studies on the influence of erythropoietin (EPO) on granulocyte or monocyte function are scant. In this study, the effect of EPO on polymorphonuclear cell (PMN) respiratory burst activity was evaluated in a double-blind, placebo-controlled study in 22 patients on maintenance hemodialysis. As an index of phagocyte respiratory burst activity, the increase in 14CO2 production from labeled glucose-1-C, after challenge with latex and zymosan, was measured on predialysis whole blood samples, before and after EPO-treatment. As controls, 56 nonuremics and 49 non-EPO-treated hemodialysis patients were evaluated. Before EPO treatment 14CO2 production was depressed to 75.7% (latex) and 54.6% (zymosan) of healthy controls (P less than 0.01). A marked improvement was observed after a mean treatment period of 4 months (latex, 115 +/- 12 to 172 +/- 14; zymosan, 178 +/- 19 to 412 +/- 36 dpm/10(3) PMN, P less than 0.01). Placebo treatment induced no changes. The improvement became more pronounced with prolongation of treatment. A significant correlation between hematocrit and 14CO2 production was observed in the EPO treatment group (latex: n = 44, r = 0.47, P less than 0.05; zymosan: n = 44, r = 0.57, P less than 0.001). No correlation was found with serum ferritin. We conclude that the depressed phagocyte glycolytic activity of hemodialyzed uremics is normalized during correction of anemia by EPO. This may be attributed to factors other than a reduction in the body iron stores.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Glucose; Granulocytes; Humans; Linear Models; Male; Middle Aged; Pentose Phosphate Pathway; Phagocytes; Phagocytosis; Recombinant Proteins; Renal Dialysis; Uremia

Anemia is already present in patients with moderate renal failure and is a major cause of the decline in exercise capacity seen in these patients. We examined the effects of erythropoietin (EPO) treatment in 12 predialytic uremic patients (EPO group: mean age 46 +/- 12 years; 6 men, 6 women) with a mean glomerular filtration rate (GFR) of 10 +/- 4 ml/min x 1.73 m2. These patients were compared to a control group of 8 patients (5 men, 3 women). The observation period was 3 months. The EPO group received 300 U/kg body weight i.v. once a week. The EPO group increased their total hemoglobin (THb) from 323 +/- 89 to 466 +/- 128 g (p less than 0.001) and their hemoglobin concentration from 86 +/- 8 to 117 +/- 11 milligrams (p less than 0.001). Their exercise capacity, measured by a standardized exercise test on a bicycle ergometer, increased from 128 +/- 45 to 147 +/- 57 W (p less than 0.01). The control group did not change their THb (349 +/- 124 and 357 +/- 131 g), hemoglobin (93 +/- 8 and 94 +/- 10 milligrams) or exercise capacity (98 +/- 49 and 101 +/- 50 W) during the observation period. There was a significant correlation between the increase in THb and the increase in exercise capacity in the EPO group (r = 0.81, p less than 0.005). The GFR was unchanged in both groups (EPO group: 10 +/- 4 and 10 +/- 6 ml/min x 1.73 m2; control group: 8 +/- 3 and 8 +/- 3 ml/min x 1.73 m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Pressure; Erythropoietin; Exercise; Female; Humans; Kidney; Male; Middle Aged; Uremia

Fifty-seven patients receiving chronic high-flux hemodialysis began receiving recombinant alpha-human erythropoietin (rHuEPO). The mean initial rHuEPO dose used in 54 evaluable patients was 9963 +/- 4364 U/week; the final dose was 8972 +/- 4058 U/week. Treatment over a mean period of 154 +/- 40 days (84 to 224 days) resulted in an average increase in hematocrit from 24.7% +/- 3.7% to 32.5% +/- 4.4%. We present a model for these data that describes changes in hematocrit during rHuEPO therapy and that allows simultaneous estimation of red blood cell lifespan and rHuEPO-induced increases in red blood cell production rate. Analysis of the hematocrit values of the patients with the model, by use of NONMEM, a computer program for analysis of population data, reveals a nonlinear dose-response relationship with large interindividual variability (coefficient of variation) of about 50%. The estimated mean red blood cell lifespan is 64 days, with interindividual variability of about 30% (coefficient of variation). The intraindividual random variability in hematocrit about its prediction is +/- 5% of the prediction. For clinical dose adjustment, we present a method that uses only simple calculations.

Topics: Anemia; Dose-Response Relationship, Drug; Erythrocyte Aging; Erythrocytes; Erythropoietin; Female; Genetic Variation; Hematocrit; Humans; Male; Recombinant Proteins; Software; Uremia

1. A randomized, partial-crossover study was conducted in uraemic patients with dialysis-associated anaemia and transfusional iron overload to evaluate the effects of desferrioxamine chelation therapy and of recombinant human erythropoietin treatment on hepatic iron storage determined by computed tomography, as well as by serum ferritin concentration and transferrin saturation. 2. Twenty-one haemodialysis patients with moderate iron overload, confirmed by values of serum ferritin concentration, transferrin saturation and hepatic computed tomography density exceeding 1000 micrograms/l, 45% and 68 Hounsfield units respectively, were randomly allocated to three groups and were followed for 12 months. 3. During the first 6 months group 1 (n = 7) received desferrioxamine chelation therapy (30 mg/kg intravenously three times a week) and group 2 (n = 7) underwent recombinant human erythropoietin treatment (36 units/kg intravenously three times a week). Thereafter, in the second 6 months of observation patients in group 1 were switched to receive recombinant human erythropoietin. Because of a poor response in the desferrioxamine-treated group in the initial 6 months, patients in group 2 continued on the maintenance dose of recombinant human erythropoietin (18 units/kg three times a week) until the end of the trial. Patients in group 3 (n = 7) were maintained on placebo throughout the study. 4. In comparison with placebo, recombinant human erythropoietin treatment, but not desferrioxamine chelation therapy, reduced serum ferritin concentration, transferrin saturation and hepatic computed tomography density, and was associated with a rise in haemoglobin and packed cell volume. Hepatic computed tomography density, serum ferritin concentration and transferrin saturation decreased in 13 out of 14 patients (93%) during treatment with recombinant human erythropoietin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Chelation Therapy; Deferoxamine; Erythropoietin; Female; Ferritins; Hemosiderosis; Humans; Iron; Liver; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Tomography, X-Ray Computed; Transferrin; Uremia

In the present study, uremic patients on chronic maintenance hemodialysis were treated with recombinant erythropoietin. Before and after 20 weeks of treatment, platelet adhesion and aggregation were studied with perfusions over a sprayed collagen surface and over matrix of cultured endothelial cells with high tissue factor activity. The influence of the erythropoietin induced raise in hematocrit on platelet transport and adhesion was excluded by performing the perfusions at a standard red blood cell concentration. The present study clearly demonstrates that erythropoietin treatment improves platelet adhesion and aggregation in addition to and independent of its effect on the hematocrit. Studies with control platelets resuspended in plasma of untreated patients showed that a uremic plasma factor reduced adhesion and thrombin- and collagen-dependent aggregation. Patient platelets resuspended in control plasma showed no defects. After erythropoietin treatment, the plasma-induced inhibition of adhesion and aggregation had almost completely disappeared from patient plasma. The beneficial effect of the erythropoietin treatment on uremic hemostasis is therefore twofold. The increase of the red blood cell mass improves transport of platelets, and thus adhesion to the vessel wall. The intrinsic defect due to the presence of an inhibitory toxin in uremic plasma is, in large part, corrected. Improved neutralization of uremic toxins by red blood cells or less production of toxins by better oxygenated tissue might play a role in the observed phenomena.

Topics: Adult; Aged; Anemia; Cells, Cultured; Collagen; Erythropoietin; Female; Fibrinopeptide A; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Perfusion; Platelet Adhesiveness; Platelet Aggregation; Recombinant Proteins; Uremia

This study was designed to assess the response of growth hormone (GH) to growth hormone releasing hormone (GHRH) and the possible interaction of acutely administered recombinant human erythropoietin (rhEPO) on GH response to GHRH in a group of uraemic patients. Eight patients on maintenance haemodialysis, not previously treated with rhEPO, and six healthy controls were tested with GHRH (100 micrograms i.v. in bolus), and with GHRH (100 micrograms i.v. in bolus) plus rhEPO (40 U/kg in constant infusion for 30 min) on different days. GHRH injection provoked a GH release in five out of eight uraemic patients; the overall mean response did not differ significantly from the GH response obtained in controls (P = 0.30). Erythropoietin infusion significantly increased GH release after GHRH (P less than 0.01 at 15, 30, 45, 60 min after GHRH injection) in uraemic patients; in controls, on the contrary, stimulation with GHRH plus rhEPO did not induce a greater increase of GH release compared with that observed after GHRH alone (mean GH peak 37.66 +/- 7.68 mU/l after GHRH; and 38.0 +/- 9.18 mU/l after GHRH plus rhEPO; P greater than 0.5). In this study acutely administered rhEPO significantly potentiated the GH response to GHRH in uraemic patients whereas the same effect was not demonstrable in subjects with normal renal function.

Topics: Adult; Aged; Erythropoietin; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Prolactin; Recombinant Proteins; Renal Dialysis; Uremia

Recombinant human erythropoietin may improve hemostasis of uremic patients by correcting anemia. However, a complete correction of renal anemia carries the risk of hypertension, encephalopathy, thrombosis, and hyperkalemia. Our aim was to establish the minimum level of packed cell volume (PCV) achieved with recombinant human erythropoietin that corrects the prolonged bleeding time in uremia. Twenty patients with chronic renal failure, anemia, and very prolonged bleeding time (greater than or equal to 15 minutes) were randomly allocated to erythropoietin or no specific treatment. The initial dose of erythropoietin was 50 U/kg intravenously (IV) three times a week. Every 4 weeks, the dose was increased by 25 U/kg until a normalization of bleeding time was achieved. Erythropoietin at a dose ranging from 150 to 300 U/kg/wk induced an increase in PCV to a range of 27% to 32% in all patients but one, and normalized bleeding time in all patients. A significant negative correlation (r = 0.898, P less than 0.001) was found between PCV and bleeding time measurements. Erythropoietin also significantly (P less than 0.01) increased values for red blood cell (RBC) distribution width (basal, 11.3 +/- 0.6; 12 weeks, 13.1 +/- 1.3). Platelet count and platelet function parameters did not significantly change. In untreated patients, no changes were recorded in all the parameters considered. These results establish in a controlled fashion that erythropoietin shortens bleeding time of uremic patients and indicate that a partial correction of renal anemia is enough to normalize bleeding time.

Topics: Adult; Aged; Bleeding Time; Erythropoietin; Female; Hematocrit; Hemorrhagic Disorders; Humans; Male; Middle Aged; Platelet Count; Prothrombin Time; Recombinant Proteins; Thromboxane B2; Uremia

Twenty uremic patients on regular hemodialysis received recombinant human Erythropoietin (rhEPO) in a dosage of 50 U/kg body wt (N = 9) and 80 U/kg body wt (N = 11), respectively, three times weekly. The number of circulating hemopoietic progenitor cells colony-forming unit-granulocyte-erythrocyte-macrophage (CFU-mix), burst-forming unit-erythroid (BFU-E) and colony-forming-granulocyte-macrophage (CFU-GM) in peripheral blood were assayed weekly by means of a commonly applied in vitro clonal assay. A significant increase of peripheral CFU-mix, BFU-E and CFU-GM could be observed within one week of supplementation therapy in both groups. The increase of BFU-E was followed by a rise of hematocrit within four and three weeks, respectively. These results suggest that the stimulatory in vivo effect of rhEPO administered in therapeutical doses is not restricted to the erythroid lineage but also includes progenitor cells committed to the myeloid lineage (CFU-GM) as well as the multipotent progenitors CFU-mix. The increment of circulating progenitor cells was seen with a dosage of 80 U/kg body wt and 50 U/kg body wt as well.

Topics: Anemia; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Hematopoietic Stem Cells; Humans; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Biological Availability; Drug Administration Schedule; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Multicenter Studies as Topic; Platelet Count; Renal Dialysis; Uremia

Topics: Adult; Anemia; Clinical Trials as Topic; Erythropoietin; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Prolactin; Renal Dialysis; Sexual Dysfunction, Physiological; Testosterone; Uremia

Decreased production of erythropoietin (EPO) is a major cause of anemia associated with chronic kidney disease (CKD). Treatment with recombinant human EPO (rHuEPO) improves patients' quality of life and survival; however, there is a marked variability in response to rHuEPO. At present, no available laboratory test is capable of evaluating responsiveness to EPO treatment. The aim of the present study was to use an in vitro bioassay to estimate the effect of uremic environment on EPO-dependent erythroid cell proliferation.. EPO-dependent human erythroleukemia cells (UT-7) were incubated with exogenous EPO (2 u/ml) and sera obtained from 60 pediatric patients (aged 1-23 years). Three groups were studied: (1) 12 children on dialysis (4 peritoneal, 8 hemodialysis); (2) 28 patients with CKD 1-5 (not on dialysis), and (3) 20 healthy children.. Sera from dialysis patients inhibited UT-7 cell growth compared to the CKD group and healthy controls at 48 h (p = 0.003 and p = 0.04, respectively) and 72 h of culture (p = 0.02 and p = 0.07, respectively). In 18 patients treated with rHuEPO, a significant inverse correlation was found between the EPO resistance index and cell proliferation at 48 h (p = 0.007, r = - 0.63) and 72 h (p = 0.03, r = - 0.52).. Our findings support the presence of erythropoiesis inhibitory substances in uremic sera. EPO/EPO-R-dependent mechanisms may play a role in inhibiting erythropoiesis. The in vitro bioassay described herein may serve as an indicator of rHuEPO responsiveness which may encourage further investigation of underlying mechanisms of EPO resistance.

Topics: Adolescent; Adult; Anemia; Biological Assay; Cell Line, Tumor; Child; Child, Preschool; Drug Resistance; Erythropoiesis; Erythropoietin; Female; Humans; Infant; Male; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Uremia; Young Adult

Renal anemia is common among chronic kidney disease (CKD) patients, and is mainly caused by inadequate erythropoietin (EPO) production from kidneys due to dysfunction of intracellular hypoxia-inducible factor (HIF) signaling in renal EPO-producing cells. We have previously shown that indoxyl sulfate (IS), a representative protein-bound uremic toxin accumulated in the blood of CKD patients, inhibits hypoxia-induced HIF activation and subsequent EPO production through activation of aryl hydrocarbon receptor (AHR). In this study, we further investigated the effects of other protein-bound uremic toxins on HIF-dependent EPO expression using EPO-producing HepG2 cells. We found that indoxyl glucuronide (IG) and IS, but not p-cresyl sulfate, phenyl sulfate, 3-indoleacetic acid or hippuric acid, inhibited hypoxia mimetic cobalt chloride-induced EPO mRNA expression. Furthermore, IG at concentrations similar to the blood levels in CKD patients inhibited the transcriptional activation of HIF induced by both cobalt chloride treatment and hypoxic culture. IG also induced CYP1A1 mRNA expression and nuclear translocation of AHR protein, indicating that IG activates AHR signaling. Blockade of AHR by a pharmacological antagonist CH-223191 abolished the IG-induced inhibition of HIF activation. Collectively, this study is the first to elucidate the biological effects of IG to inhibit HIF-dependent EPO production through activation of AHR. Our data suggests that not only IS but also IG contributes to the impairment of HIF signaling in renal anemia.

Topics: Cell Survival; Cytochrome P-450 CYP1A1; Erythropoietin; Gene Expression Regulation; Glucuronates; Hep G2 Cells; Humans; Indican; Indoles; Protein Binding; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic; Signal Transduction; Transcriptional Activation; Uremia

The response of erythropoietic stimulating agents (ESA) in uremic patients may be associated with the changes of biochemical parameters, metal elements and inflammation status during the shift from one ESA to another.. We compared changes in above mentioned factors after switching from darbepoetin-α (DPO) 20μg weekly for 10 weeks to continuous erythropoietin receptor activator (CERA) 100μg monthly for 10 weeks in uremic patients on hemodialysis. The haematocrit (Hct), metal elements and inflammation status are the primary outcome. Subjects included 54 patients without transfusion or bleeding or additional ESAs. Responders (IR, n=36) were defined as patients with an increase in Hct after the swtich.. Although there was no significant difference in overall mean Hct after the switch (p=0.135), there are significantly greater mean number of red blood cells (RBC) (p=0.006), higher platelet numbers (p=0.001), larger RBCs (p=0.017) and higher creatinine (p=0.04) and total cholesterol (T-CHOL) (p=0.003) levels. Mean overall aluminium (Al) level decreased significantly (p=0.001). C-reactive protein (CRP) also decreased (p=0.016). The overall LDH increased (p=0.049) and potassium decreased significantly (p=0.036), which indicating active erythropoiesis. The calcium (Ca) level was significantly higher (p=0.034) and phosphate was significantly lower (p=0.028) after the shift. Although there was no significant increase in overall levels of parathyroid hormone (PTH) after the shift (p=0.061), but the pre-shift and post-shift PTH level was significantly higher in IRs than in non-IRs (p=0.003 and p=0.027, respectively). IRs had a significantly lower initial T-CHOL (p=0.03) and initial CRP (p=0.012) than non-responders, which may be related to lower inflammation.. We found the shift from DPO to CERA results in lower Al levels, a reduced inflammatory response, and an increase in RBC number and PTH level in uremic patients on hemodialysis.

Topics: Aged; Aged, 80 and over; Aluminum; Cholesterol; Creatinine; Darbepoetin alfa; Erythrocyte Count; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Parathyroid Hormone; Platelet Count; Polyethylene Glycols; Renal Dialysis; Uremia

Recent observations in end-stage renal disease (ESRD)-patients on hemodialysis revealed that anemia is, in part, due to stimulated suicidal erythrocyte death or eryptosis leading to accelerated clearance of circulating erythrocytes. The present study explored whether eryptosis is similarly enhanced in patients on peritoneal dialysis (PD).. Measurements were made in freshly drawn erythrocytes from healthy volunteers (n=38), and ESRD patients on hemodialysis (HD; n=18) or on PD (n=22). Both, HD patients and PD patients suffered from anemia despite increased reticulocyte numbers.. The percentage of phosphatidylserine-exposing erythrocytes was significantly higher in HD patients than in healthy volunteers and significantly higher in PD patients than in healthy volunteers and HD patients. In PD patients, the percentage of phosphatidylserine-exposing erythrocytes was positively correlated with dialysis volume. The increase in phosphatidylserine exposure was in both, HD and PD patients, paralleled by increase of reactive oxygen species and ceramide abundance. In both, HD and PD patients, a positive correlation was observed between the percentage of phosphatidylserine-exposing erythrocytes and both, erythropoietin dosage and the percentage of reticulocytes.. Similar to HD patients, PD patients suffer from enhanced eryptosis, which is paralleled by oxidative stress and enhanced ceramide abundance contributing to the anemia of uremic patients.

Topics: Adult; Apoptosis; Cell Death; Ceramides; Erythrocytes; Erythropoietin; Female; Humans; Male; Middle Aged; Oxidative Stress; Peritoneal Dialysis; Phosphatidylserines; Reactive Oxygen Species; Renal Dialysis; Renal Insufficiency; Uremia

The objective of this study is to investigate the serum beta-2-microglobulin (B2MG) and advanced oxidation protein products (AOPP) as middle molecule uremic toxins and protein carbonyl (PCO) as oxidative stress marker in uremic patients undergoing high-flux versus low-flux hemodialysis (HD) and to correlate their levels to the erythropoietin requirements for those patients. Twenty patients on chronic low-flux HD were recruited in the study. At the start of the study, all patients underwent high-flux HD for eight weeks, followed by low-flux HD for two weeks as a washout period. The patients were then subjected to another eight weeks of low-flux HD. Blood samples were obtained at the beginning and at the end of the high-flux period and the low-flux period. The mean erythropoietin dose for patients using high-flux HD was significantly lower than that for low-flux HD (P = 0.0062). Post-high flux, the B2MG and PCO levels were significantly lower than the pre-high-flux levels (P = 0.026 and 0.0005, respectively), but no significant change was observed in AOPP (P = 0.68). Post-low flux, the B2MG, AOPP and PCO were significantly higher than the pre-low-flux levels (P = 0.0002, 0.021 and <0.0001, respectively). Post-low flux, the B2MG and PCO were significantly higher than the post-high-flux levels (P <0.0001), but no significant difference was observed in AOPP (P = 0.11). High-flux HD results in reduction of some of the middle molecule toxins and PCO levels better than low-flux HD, and is associated with a better response to erythropoietin.

Topics: Advanced Oxidation Protein Products; beta 2-Microglobulin; Cross-Over Studies; Erythropoietin; Female; Humans; Male; Membranes, Artificial; Oxidative Stress; Protein Carbonylation; Renal Dialysis; Toxins, Biological; Uremia

To investigate intestinal motility changes due to uremia, and the effect of pretreatment with erythropoietin.. This randomized control study was conducted in the Department of Physiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt from September 2010 to July 2011. Forty adult female Wistar albino rats were allocated into 3 groups: control group, gentamicin-treated group, receiving intraperitoneal gentamicin sulphate (100 mg/kg for 5 days), and erythropoietin-gentamicin-treated group, receiving subcutaneous erythropoietin (1000 IU/kg for 3 days) prior to gentamicin injection. Isolated segments of duodenum and descending colon was subjected to in vitro motility study. Plasma creatinine and urea were assayed.. Induction of acute renal failure by gentamicin treatment resulted in a significant decrease in frequency of contraction of the duodenum and descending colon, an increase in the average duration of contraction of the duodenum, and a significant decrease in the average force of contraction in the descending colon. Moreover, the average force of contraction in response to acetylcholine was significantly decreased in the duodenum. The erythropoietin-gentamicin-treated group revealed a significant decrease in plasma creatinine and urea, and a significant increase in the duodenal average force of contraction and motility index, and colonic frequency. The duodenal absolute and average forces of contraction after acetylcholine increased significantly.. Acute uremia impairs small and large intestinal motility, probably due to uremic toxins and autonomic dysfunction. Erythropoietin pretreatment protected against intestinal dysmotility through the improvement of renal function and its neurotropic action.

Topics: Acute Disease; Animals; Colon; Creatinine; Disease Models, Animal; Duodenum; Erythropoietin; Female; Gastrointestinal Motility; Gentamicins; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Uremia

Relative deficiency in production of glycoprotein hormone erythropoietin (Epo) is a major cause of renal anemia. This study planned to investigate whether the hypoxia-regulated system of Epo expression, constructed by fusing Epo gene to the chimeric phosphoglycerate kinase (PGK) hypoxia response elements (HRE) in combination with cytomegalovirus immediate- early (CMV IE) basal gene promoter and delivered by plasmid intramuscular injection, might provide a long-term physiologically regulated Epo secretion expression to correct the anemia in adenine-induced uremic rats. Plasmid vectors (pHRE-Epo) were synthesized by fusing human Epo cDNA to the HRE/CMV promoter. Hypoxia-inducible activity of this promoter was evaluated first in vitro and then in vivo in healthy and uremic rats (n = 30 per group). The vectors (pCMV-Epo) in which Epo expression was directed by a constitutive CMV gene promoter served as control. ANOVA and Student's t-test were used to analyze between- group differences. A high-level expression of Epo was induced by hypoxia in vitro and in vivo. Though both pHRE-Epo and pCMV-Epo corrected anemia, the hematocrit of the pCMV-Epo-treated rats exceeded the normal (P < 0.05), but that of the pHRE-Epo-treated rats didn't. Hypoxia-regulated system of Epo gene expression constructed by fusing Epo to the HRE/CMV promoter and delivered by plasmid intramuscular injection may provide a long-term and stable Epo expression and secretion in vivo to correct the anemia in adenine-induced uremic rats.

Topics: Anemia; Animals; Base Sequence; Blood Urea Nitrogen; Cell Hypoxia; Creatinine; Erythropoietin; Gene Expression Regulation; Genes, Reporter; Genetic Therapy; HeLa Cells; Humans; Injections, Intramuscular; Kidney; Luciferases, Firefly; Molecular Sequence Data; Plasmids; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Response Elements; Transcriptional Activation; Uremia

Advanced chronic kidney disease (CKD) patients encounter anemia through insufficient erythropoietin (EPO) production by peritubular fibroblasts. Recent studies showed an increase in EPO production by pharmacological activation of hypoxia-inducible transcription factors (HIFs) in dialysis patients, suggesting that desensitization of the oxygen-sensing mechanism is responsible for the development of renal anemia. Our recent work demonstrated that indoxyl sulfate (IS), a uremic toxin, dysregulates oxygen metabolism in tubular cells. Here we provide evidence of an additional property that IS impairs oxygen sensing in EPO-producing cells. HepG2 cells were stimulated with cobalt chloride (CoCl(2)) or hypoxia under varying concentrations of IS. EPO mRNA was evaluated by quantitative PCR. Nuclear accumulation of HIF-α was evaluated by western blotting. Transcriptional activity of HIF was checked by hypoxia-responsive element (HRE)-luciferase reporter assay. The impact of IS was further evaluated in vivo by administering rats with indole, a metabolic precursor of IS, and subjecting them to CoCl(2) stimulation, in which renal EPO mRNA as well as plasma EPO levels were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively. Although IS induced cellular toxicity at relatively high concentrations (2.5 mM), EPO mRNA expression was significantly suppressed by IS at concentrations below cytotoxic ranges. In HepG2 cells, IS treatment decreased nuclear accumulation of HIF-α proteins and suppressed HRE-luciferase activity following hypoxia. Furthermore, administration of rats with indole suppressed renal EPO mRNA expression and plasma EPO levels, corroborating in vitro findings. Results of the present study provide a possible connection between a uremic toxin and the desensitization of the oxygen-sensing mechanism in EPO-producing cells, which may partly explain inadequate EPO production in hypoxic kidneys of CKD patients.

Topics: Animals; Blotting, Western; Cobalt; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Gene Expression Regulation; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1; Indican; Indoles; Kidney Failure, Chronic; Luciferases; Oxygen; Rats; Uremia

Erythropoietin (EPO) administration in uremic rats leads to an increase in blood pressure (BP). Because chronic renal failure has been associated with oxidative stress, we hypothesize that EPO treatment could accentuate this condition and contribute to hypertension. The present study was designed to investigate the role of reactive oxygen species in EPO-induced hypertension and the effect of tempol, a superoxide dismutase-mimetic.. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 3-week stabilization period. Uremic rats were divided into four groups and received for 4 weeks: vehicle; EPO (100 U/kg, subcutaneously, three times per week); vehicle + tempol (1 mmol/l in drinking water); and EPO + tempol. Systolic BP and biochemical parameters were assessed before and at the end of the treatment. Renal histology, creatinine clearance rate, endothelin-1 (ET-1) concentrations and superoxide anion production were assessed at the end of the study.. The uremic rats developed anemia and hypertension. ET-1 concentrations and superoxide anion production were increased. EPO administration corrected anemia, but accentuated hypertension and renal injuries such as glomerulosclerosis, interstitial fibrosis, and inflammation. EPO therapy further increased tissue levels of ET-1 and superoxide anion production. Tempol treatment improved hypertension and renal injury, and reduced ET-1 concentrations and superoxide anion production.. Oxidative stress contributes to the development of hypertension and to the progression of renal injuries in uremic rats. EPO administration further increases oxidative stress, which might partly account for the accentuation of hypertension and renal injury.

Topics: Anemia; Animals; Blood Pressure; Endothelin-1; Erythropoietin; Hypertension; Kidney Failure, Chronic; Male; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins; Uremia

Renal anaemia is a common early complication of chronic renal failure (CRF) that is characterized by relative erythropoietin (EPO) deficiency. Although a lowered renal function is considered to induce limited EPO production, potential EPO production capacity in CRF remains unclear. The aim of this study was to determine the mechanisms underlying this relative deficiency.. Male Sprague-Dawley rats were underwent 5/6 nephrectomy with different severities of CRF. These rats were assigned to two groups - mild CRF or advanced CRF - and subjected to haemodilution by exchange of blood with Ringer's solution or haemoconcentration by blood transfusion. Serum EPO and EPO transcript levels in remnant kidney were examined. Expression levels of hypoxia-related genes, including heme oxygenase-1 (HO-1) and glucose transporter-1 (Glut-1), were also examined.. Haemodilution increased both serum EPO and EPO transcript levels in mild CRF, as observed in sham-operated controls, whereas the extents of such increases were significantly smaller in advanced CRF. HO-1 and Glut-1 transcript levels also increased by haemodilution in mild CRF, but not in advanced CRF. Haemoconcentration markedly decreased serum EPO and EPO transcript levels in mild CRF as in controls. Rats with advanced CRF did not survive after blood transfusion.. Potential EPO regulation capacity in mild CRF is as conserved as that in normal control, whereas that in advanced CRF is impaired, suggesting that underlying mechanisms of low EPO production alters according to the stage of CRF.

Topics: Animals; Erythropoietin; Kidney; Male; Rats; Rats, Sprague-Dawley; Uremia

Circulating erythropoietin (EPO) is mainly produced in the kidneys, depending on blood oxygen level. The present study investigated the postmortem serum EPO levels with regard to the cause of death and survival time. Serial medicolegal autopsy cases of postmortem time within 48 h (n = 536) were examined. Serum EPO levels were within the clinical reference range in most cases. Uremic patients with medical administration of an EPO agent (n = 11) showed a markedly high level (140-4,850 mU/ml; median, 1,798 mU/ml). Otherwise, an elevation in serum EPO level (>30 mU/ml) was mainly seen in protracted deaths due to blunt injury and fire fatality, depending on the survival time (r = 0.69, p < 0.0001, and r = 0.45, p < 0.0001, respectively), and in subacute deaths from gastrointestinal bleeding and infectious diseases. However, mildly to moderately elevated serum EPO levels were sporadically found in acute deaths due to mechanical asphyxiation, fire fatality, and acute ischemic heart disease, and in fatal hypothermia cases, especially for elderly subjects. Protracted deaths due to mechanical asphyxiation and ischemic heart disease did not show any survival time-dependent increase in serum EPO level (p > 0.05). EPO was immunohistochemically detected in the tubular epithelia and interstitial cells, showing no evident difference among the causes of death, independent of survival time or serum level. These findings suggest that serum EPO can be used as a marker for investigating anemia and/or hypoxia as a consequence of fatal insult in subacute or prolonged deaths, or a predisposition to traumatic deaths or fatal heart attacks in acute deaths.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asphyxia; Biomarkers; Communicable Diseases; Drowning; Erythropoietin; Female; Fires; Forensic Pathology; Gastrointestinal Hemorrhage; Humans; Hypothermia; Immunohistochemistry; Kidney; Male; Middle Aged; Myocardial Ischemia; Postmortem Changes; Sensitivity and Specificity; Time Factors; Uremia; Wounds, Nonpenetrating; Young Adult

Recombinant human erythropoietin (rHuEPO) is the cornerstone of anaemia therapy in uraemic patients however the effects of this hormone on fibrinolytic system are difficult to interpret.. Assessment of fibrinolytic parameters: tissue-type plasminogen activator (tPA) antigen, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR), plasminogen activator inhibitor 1 (PAI-1) and plasmin/antiplasmin (PAP) complexes were performed in haemodialyzed (HD) patients without rHuEPO therapy: Group I (n=8, Hg<10 g/dl); Group II (n=12, Hg>10 g/dl); and in HD patients treated with rHuEPO for more than 6 months (Group III, n=10) or for more than 12 months (Group IV, n=9) in relation to the healthy controls.. Patients of Group I had the significantly lower haematological parameters than those of Groups II, III and IV. All the fibrinolytic parameters studied, except PAI-1, were significantly higher in HD patients without rHuEPO therapy when compared to the controls. There were no significant differences in fibrinolytic system between the Groups I and II. Erythropoietin therapy resulted in progressive decrease in antigenic tPA levels, which reach normal range values after 6 months rHuEPO administration. uPA and PAP concentrations were also decreased and reached normal values after 12 months of rHuEPO therapy. In these patients a significant decrease in uPAR levels was also observed. Therapy with rHuEPO did not alter PAI-1 concentrations in HD patients.. These results suggest that long-term rHuEPO therapy can correct fibrinolytic parameters in patients undergoing regular HD irrespective from haemoglobin levels and in the absence of concomitant iron supplementation.

Topics: alpha-2-Antiplasmin; Anemia; Erythropoietin; Female; Fibrinolysin; Fibrinolysis; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Recombinant Proteins; Reference Values; Renal Dialysis; Sensitivity and Specificity; Time; Tissue Plasminogen Activator; Treatment Outcome; Uremia; Urokinase-Type Plasminogen Activator

Intravenous iron supplementation is a recognized therapy for anemia in chronic hemodialysis patients, especially in those treated with erythropoietin. The vast majority of patients with chronic kidney disease (CKD) seem to be iron-deficient, as evaluated by the usual parameters and by iron staining on bone marrow biopsy, because of multiple forms of interference with all phases of iron metabolism. The need for iron supplementation in CKD patients becomes obvious. Intravenous iron was demonstrated to be superior to oral iron in hemodialysis patients. There is also evidence for the superiority of intravenous iron in peritoneal dialysis and in nondialysis-dependent CKD patients. On the other hand, intravenous iron could promote cytotoxicity and tissue injury, and exacerbate oxidative stress and thus endothelial dysfunction, as well as inflammation and the progression of both CKD and cardiovascular disease. Nevertheless, correction of anemia is effective in reducing oxidative stress and, consequently, cardiovascular risk. The overall risk-benefit ratio favors the use of intravenous iron alone or with an erythropoietic stimulating agent in the management of renal anemia. Clinical judgment is necessary in each individual case to diagnose iron deficiency and effectively use intravenous iron.

Topics: Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Humans; Inflammation; Injections, Intravenous; Iron; Kidney Failure, Chronic; Oxidative Stress; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Risk Assessment; Uremia

Topics: Anemia; Erythropoiesis; Erythropoietin; History, 19th Century; History, 20th Century; Humans; Hypoxia; Neoplasms; Recombinant Proteins; Uremia

Topics: Carnitine; Drug Therapy, Combination; Erythrocytes; Erythropoietin; Humans; Renal Dialysis; Thalassemia; Treatment Outcome; Uremia; Vitamin B Complex

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in the atherosclerosis. Recombinant human erythropoietin (EPO) has become widely used to treat anemic hemodialyzed (HD) patients; however, an increased mortality has been reported for HD patients with cardiovascular disease when randomly assigned to normal hematocrit by EPO. Therefore, we conducted a study examining the effect of EPO on MMPs/TIMPs system, oxidative stress and inflammation in these patients.. Assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2 were performed in 20 stable HD patients and 15 healthy controls. Additionally, the effects of EPO on malondialdehyde (MDA)--a marker of SOX and C-reactive protein (CRP) levels--as a marker of inflammation were also investigated. Of the 20 patients, 10 were receiving EPO therapy [HD-EPO(+)] for 12 months or more and 10 were not receiving EPO therapy [HD-EPO(-)]. Both groups were not receiving iron supplementation.. All parameters, with the exception of MMP-9, were lower in the healthy subjects compared with the HD subjects, irrespective of EPO administration. There was no difference in MMPs/TIMPs system, MDA and C-reactive levels between HD-EPO(+) and HD-EPO(-) patients.. Erythropoietin therapy did not influence MMPs/TIMPs system, inflammation, or SOX in a low-risk HD patient population, in the absence of concomitant iron supplementation and mean Hg levels within target.

Topics: Adult; Aged; Anemia; C-Reactive Protein; Case-Control Studies; Erythropoietin; Female; Humans; Male; Malondialdehyde; Metalloproteases; Middle Aged; Oxidative Stress; Renal Dialysis; Tissue Inhibitor of Metalloproteinases; Uremia

Topics: Aged; Anemia; Cost-Benefit Analysis; Darbepoetin alfa; Drug Costs; Erythropoietin; Female; Hematinics; Humans; Male; Recombinant Proteins; Uremia

In hemodialysis patients, left ventricular hypertrophy (LVH) correlates with mortality. The reason for LVH in uremics is multifactorial. The primary objective of our study was to investigate the effects of a multi-interventional treatment strategy on LVH.. In 230 ambulatory patients, including patients with coronary artery disease, diabetes, diastolic and systolic dysfunction, we continued optimized cardiac therapy (beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) with full anemia correction by intravenous epoetin-beta. The dose of epoetin-beta for maintaining target hemoglobin (Hb) was 68 +/- 23 IU/kg/week. Serial echocardiograms were recorded every 3-6 months. The mean observation period was 4.8 +/- 1.2 years.. Mean Hb at baseline was 11.2 +/- 2.0 versus 14.1 +/- 1.4 g/dl (p < 0.001) at study end. There was a significant reduction in left ventricular mass index (LVMI: 159 +/- 50.4 vs. 130.2 +/- 42.7 g/m(2); p < 0.001). In a subgroup of 2/3 of the patients, LVMI returned to normal (169 +/- 33 vs. 114 +/- 14 g/m2; p < 0.001).. Baseline LVMI (p < 0.001), Hb increase (p < 0.03), and triple cardiac therapy (p < 0.03) were significant and independent prognostic factors for a reduction in LVMI. The annual cardiovascular mortality was 5%. Even anemia correction from 12 to 14 g/dl results in further (p < 0.001) regression of LVMI.

Topics: Aged; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Erythropoietin; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Anemia is an inevitable consequence of chronic renal failure. Gene therapy using lentiviral vector (LV) would be an effective tool to treat anemia associated with renal failure.. A LV carrying the erythropoietin (EPO) cDNA was administered to skeletal muscle of partially nephrectomized rats, which is a model of uremia. The red blood cell production and serum EPO levels were temporally monitored in these rats. Polymerase chain reaction assays were done to validate the presence of the LV in the experimental rats.. After a single intramuscular injection of LV at a dose of 55 microg p24 Gag antigen (approximately 5 x 10(7) transducing units), blood hematocrit (Hct) levels increased and peaked at 3 weeks (47.8 +/- 4.2%, p < 0.01, n = 8) with the levels being maintained for at least 20 weeks (duration of study; 44.9 +/- 3.3%, p < 0.01, n = 3). The control rats receiving LV expressing lacZ had Hct levels of 36.9 +/- 4.1% (n = 8) at 3 weeks and 33.1 +/- 3.7% (n = 4) at 20 weeks, respectively. The serum EPO levels in the rats injected with the LV expression EPO significantly increased (p < 0.01) to 156.3 +/- 3.0 mU/ml compared to the control rats (63.9 +/- 1.7 mU/ml). Polymerase chain reaction analysis of the isolated genomic DNA from the LV-injected rats showed specific positive detection of the LV in only the skeletal muscle tissue at the site of injection, whereas the other tissues, including the liver, spleen, and kidney, were negative.. This study demonstrates that intramuscular injection of LV can produce highly efficient and sustained EPO secretion in uremic rats, and suggests that this approach could be an effective tool to deliver secretable proteins at therapeutic levels in various animal disease models.

Topics: Anemia; Animals; Erythropoietin; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Injections, Intramuscular; Kidney Failure, Chronic; Lentivirus; Male; Rats; Rats, Sprague-Dawley; Treatment Outcome; Uremia

CC-chemokines are now widely accepted in the recruitment of leukocytes from the blood compartment into tissues, and their role in the progression of atherosclerosis has been documented. Recombinant human erythropoietin (EPO) has become widely used to treat anemic HD patients. However, little is known about the effect of EPO on the plasma CC-chemokine levels and intima-media thickness (IMT) in HD patients.. Assessment of CC-chemokines: monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta), regulated upon activation, normal T cell expressed and secreted (RANTES) and IMT were performed in 26 stable HD patients and 15 healthy controls. The patients were divided into 3 groups: group I (n = 8, without EPO), group II (n = 9, EPO at a mean dose of 76 +/- 48 U/kg/week for more than 4 months), and group III (n = 9, EPO at a mean dose of 110.5 +/- 21 U/kg/week for more than 12 months), none of them on iron therapy.. MCP-1, MIP-1alpha, MIP-1beta and IMT values were significantly higher, whereas RANTES were significantly lower in HD patients without EPO therapy than those in healthy controls. CC-chemokine levels were found to be significantly lower in patients administered EPO when compared to subjects without EPO. In the patients treated with EPO for more than 12 months IMT values were significantly decreased compared to patients not receiving this hormone.. These results suggest that long-term EPO therapy decreased CC-chemokine and IMT values in patients undergoing regular HD in the absence of concomitant iron supplementation.

Topics: Atherosclerosis; Carotid Arteries; Chemokines, CC; Erythropoietin; Female; Humans; Male; Middle Aged; Renal Dialysis; Tunica Intima; Tunica Media; Uremia

Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy.. Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study.. The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction.. Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Captopril; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Hydralazine; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Losartan; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renin-Angiotensin System; Reserpine; Time Factors; Uremia

The national and international recommendations concerning the iron management in chronic kidney disease (CKD) patient are well established. All acknowledge the fact that iron needs are increased in uremic patients. This is particularly true for CKD-5 patients treated by hemodialysis (increased losses) and when treated by an erythropoetic stimulating agent (ESA). Annual iron requirements are currently estimated between 500 mg and 3000 mg per year. The biodisponibility of oral iron isreduced and side effects are quite common. The venous supplementation of iron offers today the best safety/efficacy profile. The evaluation of iron store is mandatory in CKD patient. The assessment of iron store in kidney patient relies on three major markers: transferrin saturation (Trf Sat); ferritin; percentage of hypochromic erythroid cells. Faced to iron deficiency, it is crucial to differentiate two situations: an absolute iron deficiency (Trf Sat < 20 % ; ferritin < 100 ng/ml; percentage of hypochromic cells > 10%); a functional iron deficiency (Trf Sat < 20%; ferritin > 200-500 ng/ml; percentage of hypochromic cells > 5-10%). When intravenous iron supplementation is indicated, dosing regime should be based on a slow and a reduced dosage administration to comply with manufacturer and best practice recommendations. Regular iron infusion of 50 to 100 mg per week is able to cover the basic needs for most hemodialysis patients.

Topics: Erythropoietin; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis; Transferrin; Uremia

Topics: Aged; Aged, 80 and over; Anemia; Antihypertensive Agents; Comorbidity; Erythropoietin; Female; Home Care Services, Hospital-Based; Hospitalization; Hospitals, University; House Calls; Humans; Hypertension; Kaplan-Meier Estimate; Male; Middle Aged; Nephrology; Palliative Care; Prospective Studies; Pruritus; Severity of Illness Index; Spain; Survival Rate; Terminal Care; Uremia; Water-Electrolyte Imbalance

Most patients with chronic renal failure have anemia, which can be corrected by recombinant human erythropoietin (rHuEpo) treatment. Increase in arterial pressure (AP) was reported in some studies and was related to higher systemic vascular resistance induced either by the rise of erythrocyte mass or the change in various endogenous vasopressors, including the direct action of rHuEpo itself. We investigated the effect of rHuEpo treatment on hemodynamic variables, including small and large arterial compliance in 20 patients with chronic renal failure who were not receiving dialysis (CCT 29 +/- 12 mL/min), with Hb levels of 40.4 +/- 0.58 g/dL. They were treated with 2,000 units intravenously followed by 80 to 120 s/c units/kg/body weight, with dosage titration according to Hb level. Noninvasive hemodynamic evaluation was performed before the first rHuEpo treatment, 30 min after the first IV rHuEpo administration and at least 3 months later when target hemoglobin (Hb) and hematocrit (Hct) were reached. No rise in AP occurred after rHuEpo administration either short term or long term. The significant hemodynamic changes were a fall in pulse pressure and a rise in large artery compliance, with no change in small artery compliance after 3 months of rHuEpo treatment when Hb and Hct levels were corrected. These findings show improvement in arterial stiffness when Hb is corrected with rHuEpo treatment.

Topics: Aged; Anemia; Erythropoietin; Female; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Time Factors; Uremia; Vascular Resistance

Normochromic normocytic anemia is common in children with chronic renal failure (CRF) when their glomerular filtration rate is below 35 ml/min/1.73 m2 BSA, but it may develop earlier in some forms of renal disease. An inadequate erythropoiesis due to insufficient erythropoietin synthesis in the kidneys is the main cause of renal anemia. Other reasons include reduced red blood cell lifespan, chronic blood loss, iron deficiency, inhibitors of erythropoiesis, and malnutrition. The presence of anemia contributes to many of the symptoms of uremia, including decreased appetite, decreased energy, poor cardiac function, and poor school performance. Therefore, correction of anemia dramatically improves the life of the child with CRF. Presently, the goal of anemia management is to maintain hematocrit concentrations at 33% to 36% and a hemoglobin concentration of at least 11 g/L. This can be accomplished by intravenous or subcutaneous administration of recombinant erythropoietin (rHuEPO, 100-300 U/kg/week) and iron preparations. If adequate iron stores cannot be maintained with oral therapy (2-3, max 6 mg/kg/day), intravenous iron should be administered. In order to optimize anemia management in children with CRF, future research should be concentrated on the normalization of hemoglobin early in the course of CRF, and the long-term effects on the child's development.

Topics: Anemia; Child; Erythropoietin; Hemoglobins; Humans; Hypertension; Iron; Kidney Failure, Chronic; Uremia

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

Iron balance is critical for adequate erythropoiesis, but its optimal therapeutic regimen remains to be defined. Continuous maintenance therapy with iron has been proposed for dialysis patients on recombinant human erythropoietin (rHuEpo) in the hope that the regimen is adequate and safe.. We determined serum ferritin, transferrin, transferrin saturation (TSAT), serum transferrin receptors, albumin and C-reactive protein (CRP) in a 3-year prospective study in 30 chronic haemodialysis patients on dialysis treatment for 132+/-111 months (18 males, 12 females; mean age 56+/-14 years). Beginning in the year 2000, they regularly received low-dose maintenance iron supplementation (i.v. iron gluconate 31.25 mg/week) for 12 months (Period 1 or first treatment phase), followed by a 6-month withdrawal (Period 2 or stop phase) and then by continuous maintenance iron therapy (i.v. iron gluconate 31.25 mg/week) for another 9 months (Period 3 or re-challenge phase).. A significant increase in serum ferritin and TSAT was observed, with values exceeding 500 ng/ml and 50% in 10/30 (33%) and 7/30 (23%) of subjects, respectively, in Period 1, and in 11 and 5% in Period 3. A significant decrease in serum transferrin was documented during Period 1, followed by an increase in Period 2 and a decrease in Period 3. Serum albumin remained stable. Serum transferrin was always negatively correlated with ferritin (r = -0.41, P<0.001) and weakly correlated with serum transferrin receptors (r = 0.178, P<0.05), but was not correlated with serum albumin or CRP. Regression equations based on pre-treatment serum ferritin values were developed for predicting the value of serum ferritin at any time following the beginning of continuous iron supplementation. They fitted a linear relationship for males (y = 81 + 21.5 x time) and for females (y = 65 + 22 x time). Percentile charts for quantitative tracking of serum ferritin increases and decreases in patients have also been developed from values measured at different times. These charts show box-plot distributions of expected ferritin against time.. Even continuous low-dose maintenance iron therapy, with only 31.25 mg weekly over 1 year, cannot prevent the risk of iron overload in patients with moderate anaemia. Furthermore, this treatment is responsible for decreases in serum transferrin, unrelated to changes in serum albumin, possibly of concern for hypo-transferrinaemia as an independent risk factor for iron toxicity.

Topics: Aged; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematinics; Humans; Injections, Intravenous; Iron; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Transferrin; Uremia

Topics: Adult; Cardiovascular Diseases; Decision Making; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Glomerulosclerosis, Focal Segmental; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Morbidity; Neoplasms; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; Risk Assessment; Uremia

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48 U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P < 0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P < 0.01). Compared with U, UH has lower HW/BW and LV/BW (P < 0.05) and UE has normal HW/BW but lower LV/BW than U (P < 0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal a- actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta1, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure-overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.

Topics: Actins; Anemia; Animals; Atrial Natriuretic Factor; Erythropoietin; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

Under normal conditions, inflammatory status is regulated by a complex equilibrium between plasma and intracellular mediators. This equilibrium is broken in patients receiving dialysis, which can lead to chronic inflammation causing deleterious consequences on their organs and systems. During recent years, substances that can inhibit the effects of inflammation have been sought. The results of these investigations have produced controversial data on the effects of recombinant human erythropoietin (epoetin) and, in this review, the effects of epoetin on the inflammatory status of dialysis patients are discussed. Aspects discussed include biomarkers of inflammation, and the relationships between epoetin, growth factors, endothelial dysfunction, endothelial fibrinolytic capacity, endothelial damage and oxidative stress. Relationships between epoetin and inflammation in non-uraemic patients are also addressed, as are associations between the malnutrition-inflammation-atherosclerosis syndrome and endothelial dysfunction. It is concluded that although epoetin administration in non-uraemic rats has been shown to have an anti-inflammatory and cytoprotective effect, the mechanisms responsible for regulating inflammation in uraemia are very complex and partially contradictory. The changes in pro-thrombotic and pro-atherogenic factors in dialysis patients require further study to evaluate all the factors implicated in the atherogenic process.

Topics: Animals; Arteriosclerosis; Biomarkers; Endothelium, Vascular; Erythropoietin; Humans; Kidney; Plasminogen Activator Inhibitor 1; Rats; Recombinant Proteins; Renal Dialysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Uremia

Topics: Blood Platelet Disorders; Blood Platelets; Calpain; Caspases; Dialysis; Erythropoietin; Hemolytic-Uremic Syndrome; Humans; Phosphatidylserines; Platelet Activation; Platelet Aggregation; Renal Dialysis; Thrombophilia; Thrombopoiesis; Uremia

The recommended conversion dose for changing from epoetin alfa to darbepoetin alfa is 200 units to 1 microg. However, this may result in the over treatment of uraemic anaemia.. All in-centre haemodialysis patients (n = 60) were converted from an existing subcutaneous epoetin alfa regimen to weekly intravenous darbepoetin alfa. The protocol for anaemia management included a target haemoglobin (Hb) concentration of 120-130 g/L and a ferritin of 300-600 microg/L. Patient treatments were converted from subcutaneous epoetin alfa to weekly, intravenous darbepoetin alfa at month 0, at a conversion dose of 200 units epoetin alfa to 1 microg darbepoetin.. Both Hb and ferritin concentrations remained within the target range, but darbepoetin dosages fell from 50.8 to 42.3 microg/week by month 3 (P = 0.02). The initial conversion factor of 210 units/microg rose to 275 units/microg (P = 0.01) at month 4. No difference in conversion dosage could be determined between patients who were epoetin sensitive (<200 units/kg per week) or resistant (>200 units/kg per week, P = NS). Patients were then switched to fortnightly darbepoetin alfa dosing treatments; the existing weekly dose being doubled and Hb levels fell from 125 to 110 g/L (P < 0.0001), despite an increase in the mean dose from 44.9 to 47.5 microg/week (P = 0.02).. The original dosage reduction after the switch from epoetin alfa to weekly intravenous darbepoetin alfa may offset the increased relative cost of the latter. When administered weekly and intravenously, darbepoetin alfa maintains Hb at a more favourable conversion rate than is currently recommended.

Topics: Anemia; Darbepoetin alfa; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

The sudden interruption of recombinant human erythropoietin (rHuEPO) in end-stage renal disease (ESRD) patients leads to rapid anemization. The mechanisms of this phenomenon are, however, insufficiently understood. The present study examined the response to immediate rHuEPO withdrawal in dialysis patients.. 10 chronic hemodialysis (HD) patients regularly receiving rHuEPO were studied. rHuEPO was stopped and reinitiated after 7 days. Reticulocyte profile, haemoglobin and haematocrit were measured at 0, 7 and 15 days. As a complementary study, and with the purpose of analyzying whether uremia was a relevant factor, 10 non-uremic male Wistar rats were treated with rHuEPO. After two weeks, rHuEPO was withdrawn in 5 animals, and continued for 7 additional days in the remainder. The same variables than in the human study were determined.. Changes in reticulocyte subtypes from baseline to day 7 were: total 18.2 +/- 0.9 vs 14.3 +/- 1.8% (p < 0.06); high-fluorescence (HFR): 2.6 +/- 0.4 vs 0.75 +/- 0.2 (p < 0.001); medium-fluorescence (MFR): 13.0 +/- 1.1 vs 6.6 +/- 0.9% (p < 0.02); and low-fluorescence (LFR): 84.2 +/- 1.4 vs 92.7 +/- 1% (p NS). The baseline pattern was recovered upon 7 days of rHuEPO reinitiation (p NS). Mean hemoglobin and hematocrit decreased by day 14 (p < 0.02) in spite of rHuEPO reinitiation at day 7. In non-uremic rats, changes were similar to that in the ESRD patients.. rHuEPO induces changes in the reticulocyte pattern, consisting in a reduction of immature reticulocytes. These changes appear to be independent of the presence of uremia. Accordingly, complete rHuEPO withdrawal in HD patients will cause a rapidly-developing anaemia due to an alteration in the reticulocyte maturation series; therefore, sudden rHuEPO interruption should be avoided whenever is possible. As a collateral application, the specific changes described herein have potential use for detecting illegal administration of rHuEPO.

Topics: Aged; Anemia; Animals; Doping in Sports; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Rats; Rats, Wistar; Recombinant Proteins; Recurrence; Renal Dialysis; Reticulocyte Count; Uremia

Anemia has been shown to be a key component of renal failure, as well as of the occurrence of left ventricular hypertrophy (LVH), with special attention paid to the paracrine mechanism of left ventricular remodelling.. The aim of the study was to analyze possible association of serum angiotensin-converting enzyme (ACE) activity and LVH in hemodialysis patients with anemia treated with human recombinant erythropoietin (rHuEpo) during six months.. LV geometry was determined by echocardiographic analysis in 20 hemodialysis patients before and after erythropoietin treatment. Serum ACE activity was measured by spectrophotometric method using hippyril-l-histidyl-l-leucin as a substrate.. Serum ACE activity increased to 47.3% in hemodialysis patients with LVH as compared to patients with normal LV mass. A significant positive correlation was found between the level of ACE activity and LV mass index (p=0.004). Six-month erythropoietin treatment of anemia led to a significant reduction of LV mass index (p<0.008) and serum ACE activity (p=0.003) from the initial values.. The levels of serum ACE activity are associated with LV geometry. Our findings suggested the possibility of simultaneous and modest modulation of LV mass and serum ACE activity with rHuEpo correction of renal anemia.

Topics: Anemia; Erythropoietin; Humans; Hypertrophy, Left Ventricular; Peptidyl-Dipeptidase A; Recombinant Proteins; Renal Dialysis; Uremia

Recent studies suggest a possible link between recombinant human erythropoietin (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids. The current study was designed to evaluate the role of eicosanoids such as thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the relationship between these vasoactive substances in rhEPO-induced hypertension in uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 6-week stabilization period. In protocol A, rats were divided into four groups: vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks. At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto-PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia but aggravated the hypertension. Both drugs were effective in preventing the progression of hypertension in rhEPO-treated rats although ABT-627 was more potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood vessels and ABT-627 decreased tissue levels of both vasopressors. The concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly decreased tissue TXB concentrations but had no effect on ET-1 levels. These results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1) are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats. TXA probably serves as a mediator of the vascular effect of ET-1.

Topics: Animals; Eicosanoids; Endothelin Receptor Antagonists; Endothelin-1; Erythropoietin; Humans; Hypertension; Male; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Recombinant Proteins; Uremia

During peritoneal dialysis, mesothelial cells become detached from the peritoneum and accumulate in the dialysate. Our aim was to evaluate the potential of peritoneal effluent (PF)-derived human peritoneal mesothelial cells (HPMC) as target for gene therapy. We used erythropoietin (EPO) as our target gene.. Various extracellular matrixes (ECM) were tested for optimal adhesion and growth of HPMC. The EPO gene was introduced to mouse peritoneal mesothelial cells (MPMC) and HPMC by transfection or retroviral transduction. EPO secretion from PMC was measured by enzyme-linked immunosorbent assay (ELISA) and by the TF-1 cell proliferation assay. We performed intraperitoneal or intramuscular transplantations of the genetically modified cells into regular or 5/6 nephrectomized Balb/c mice and nude mice. Finally, we measured serum EPO and hematocrit levels.. ECM-coated plates provided up to sixfold increase in the efficiency of PMC isolation from PF. Gelatin coated dishes (20 microg/cm2) were found optimal for isolation of PF-HPMC. RPR-120535 liposome was found to be best for PMC transduction. In vitro studies showed EPO secretion from modified HPMC over 6 months. Intraperitoneal transplantation aided with collagen matrix was the most effective. EPO, in MPMC transplanted mice, was detected up to 3 weeks (peak at 13 +/- 1 mIU/mL), and anemia of uremic mice was corrected (35.3 +/- 0.9 mIU/mL to 41.9 +/- 1.1 mIU/mL).. PF-HPMC can be considered as an appropriate target for gene therapy since these cells can be efficiently isolated, modified, and transplanted. Nevertheless, implantation techniques in the peritoneum should be directed at obtaining longer duration of transgene expression in vivo, and means should be developed for enabling regulated expression of the gene.

Topics: Anemia; Animals; Ascitic Fluid; Cell Adhesion; Cell Division; Cell Separation; Epithelial Cells; Epithelium; Erythropoietin; Genetic Therapy; Hematocrit; Humans; Mice; Mice, Inbred BALB C; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Retroviridae; Transduction, Genetic; Transfection; Uremia

Topics: Anemia; Autoimmune Diseases; Clinical Trials as Topic; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Uremia

We report the case of a woman with end-stage renal disease on maintenance hemodialysis and treated with recombinant human erythropoietin (epoetin alfa) administered subcutaneously, who developed a pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin after 8 months of treatment. Despite epoetin withdrawal and immunosuppressive treatment with corticosteroids and gammaglobulins the patient still has high red blood cell transfusion requirements and undetectable plasma erythropoietin levels. Pure red cell aplasia secondary to the development of neutralizing antibodies anti-erythropoietin is a rare but severe complication associated with the use of recombinant human erythropoietin in uremic patients. In recent years, the incidence of this complication has sharply increased, specially associated with the use of epoetin alfa administered subcutaneously. For this reason, the Spanish Drug Agency has recently contraindicated treating uremic patients with epoetin alfa administered subcutaneously.

Topics: Adult; Autoantibodies; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Uremia

Coincidental with the pandemic growth of diabetes as the prime cause of end-stage renal disease (ESRD), blindness attributable to diabetic retinopathy has become a major concern for all those involved in the care of diabetic ESRD patients. Vision loss is linked to progression of proliferative retinopathy and macular edema.. Extracted from a study of azotemic anemic pre-ESRD patients treated with erythropoietin, a cohort of five diabetic subjects was reassessed in terms of stability of renal function, changes in blood rheology, and course of diabetic eye disease.. All subjects reported subjective improvement in well-being, including enhanced effort tolerance following an increase in hematocrit from a baseline level of to 29.6 +/- 2.0% to a level of 39.5 +/- 2.4% after one year of treatment with erythropoietin (P = <0.0005). Neither hypertension nor deterioration of renal function was noted in any subject. Three patients with macular edema evinced substantive improvement-based stable vision and documented resolution noted in flourescein angiography.. Erythropoietin treatment of anemic azotemic diabetic patients is well tolerated. In a small observational retrospective study of three patients with macular edema, retention of vision and resolution of exudates was noted.

Topics: Anemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Middle Aged; Papilledema; Uremia

Recent investigation has shown that on-line hemodiafiltration (HDF) can reduce the amount of recombinant human erythropoietin (rhEPO) deemed necessary to reach the target hematocrit. The aim of this study was to analyze the potential effect of on-line HDF on rhEPO resistance in relation to iron utilization and anemia-related parameters, when compared to conventional hemodialysis (HD).. Ninety-two chronic uremic patients were treated with conventional HD and then shifted to on-line HDF. Measurements of various erythropoiesis-related parameters were collected during HD and on-line HDF periods for statistical analysis for erythropoietin resistance.. Patients treated with on-line HDF switching from conventional HD significantly contributed to the reduction of EPO dose to reach a higher mean hematocrit level (31.8 +/- 4.4% vs. 29.5 +/- 3.9%, p < 0.001) and a reduction of the serum ferritin level (322.5 +/- 268.4 vs. 544.9 +/- 642.4, p < 0.001). The median EPO/Hct ratio was greater in the HD period (504.6 +/- 310.1) than in the on-line HDF period (307.6 +/- 334.4) (p < 0.001). These results indicated a reduced EPO resistance and improved iron utilization by on-line HDF. By multiple regression analysis, the significant predictors of EPO resistance are ferritin, transferrin, albumin, and TACurea (Time average concentration of urea) in HD treatment. In on-line HDF modality, in addition to ferritin and albumin, the duration of on-line HDF is a negative predictor in EPO resistance.. When on-line HDF is recommended to chronic dialysis patients, long-term use of this technique provides an efficient means of achieving the goal of an elevated hemoglobulin by reducing EPO resistance, improved iron utilization and may further improve the quality of life.

Topics: Chronic Disease; Drug Resistance; Erythropoietin; Female; Ferritins; Hematocrit; Hemodiafiltration; Humans; Iron; Male; Middle Aged; Online Systems; Recombinant Proteins; Serum Albumin; Transferrin; Uremia

Recent American and European guidelines recommend that epoetin therapy should be considered whenever the blood haemoglobin (Hb) level is <10-11 g/dl in dialysis patients and in pre-dialysis patients. Thus, data on the current prevalence of anaemia with respect to the degree of chronic renal insufficiency are needed in order to determine the potential indications of epoetin therapy in the pre-dialysis period.. We prospectively studied 403 consecutive ambulatory pre-dialysis patients whose serum creatinine (Scr) was 200 micro mol/l or more at their first passage at our out-patient clinic between January 1 and June 30, 1999. Hb and Scr values were determined at each visit until June 30, 2000, or until the start of maintenance dialysis. Patients had a clinical and laboratory evaluation every 2-3 months, and monthly when treated with epoetin.. The mean (+/-SD) age of patients was 60.9+/-17.2 years at presentation. The Hb level was <11 g/dl in 62% of patients with Scr > or =400 micro mol/l, and in 58% of patients with an estimated creatinine clearance (Ccr) <20 ml/min/1.73 m(2). The proportion of anaemic patients was higher for any given Ccr value in females than in males. A total of 136 patients were treated with epoetin during the observation period. At the start of epoetin, their mean Hb value was 9.5+/-0.6 g/dl and Ccr level 13.9+/-4.9 ml/min/1.73 m(2). Among the 123 patients who began maintenance dialysis therapy during the observation period, 85 (or 69%) received epoetin therapy before the start of dialysis. Their mean Hb value at the start of dialysis was 10.8+/-1 g/dl compared with 10.5+/-1.1 g/dl in the 41 dialysed patients who did not require epoetin therapy during the pre-dialysis period.. Based on the data gained in a large cohort of patients receiving regular pre-dialysis nephrological care, the proportion of subjects with a Hb level <11 g/dl may be estimated at approximately 60% when the Ccr is <20 ml/min/1.73 m(2). If the Hb level is to be maintained at no less than 11 g/dl, at least two-thirds of patients at this advanced stage of chronic renal failure should require pre-dialysis epoetin therapy.

Topics: Anemia; Creatinine; Cross-Sectional Studies; Epoetin Alfa; Erythropoietin; Female; France; Hemoglobins; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Regression Analysis; Renal Replacement Therapy; Sex Characteristics; Uremia; White People

Recombinant human erythropoietin (rHuEPO) administration has been associated with an increased risk of hypertension and thrombosis in uremic patients. rHuEPO and endothelial cells cultured in an uremic environment. Results indicate that rHuEPO does not exert an additional activating effect to that caused by the uremic media per se.

Topics: Cell Line; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Humans; Thrombosis; Uremia

Previous studies have suggested a neuroendocrine defect underlying uremic hypogonadism, characterized by a reduced secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH).. We studied the GnRH-producing GT1-7 cell line and the LH-producing LbetaT-2 pituitary cell line under uremic conditions to investigate whether substances circulating in uremic plasma directly affect hypothalamic or pituitary hormone secretion. The cells were incubated with serum from 5/6-nephrectomized or sham-nephrectomized castrated rats, respectively. Furthermore, GT1 cells were incubated with delipidated sera, serum subfractions separated by molecular weight, or several peptide hormones. Cellular viability, apoptosis rate and extracellular hormone degradation were assessed separately. GnRH and LH were measured by RIA in supernatants and cell lysates. GnRH gene expression was assessed by Northern blot.. Uremic serum caused a reduction of extracellular GnRH concentration by 31%, whereas intracellular GnRH increased by 12%. This effect was independent of serum lipids and enzymatic GnRH degradation but was abolished by trypsin digestion. Cellular viability, apoptosis rates and GnRH gene expression did not differ between the two groups. The inhibitory activity was recovered from the high-molecular weight fraction, whereas the fraction <5 kD had stimulatory activity. In contrast, uremic serum did not affect LH secretion from LbetaT-2 cells, indicating that the hypoactivity of the hypothalamo-pituitary gonadotrope unit results from an inhibition at the hypothalamic rather than the pituitary level.. Our results suggest that uremic serum contains macromolecular and hydrophilic peptide(s) able to specifically suppress the neurosecretion of GnRH from GT1-7 cells.

Topics: Animals; Blood Proteins; Cell Line; Creatinine; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression; Gonadotropin-Releasing Hormone; Growth Hormone; Hot Temperature; Hypothalamus; Insulin-Like Growth Factor I; Leptin; Luteinizing Hormone; Male; Neurons; Parathyroid Hormone; Pituitary Gland; Prolactin; Rats; Rats, Sprague-Dawley; Urea; Uremia

Clinical experience indicates that bleeding and thrombotic tendencies co-exist in uremic patients. Numerous studies have shown that platelet functional defects contribute to the bleeding tendency in uremic patients. In contrast, there are no solid studies clarifying the pathogenesis of the prothrombotic state in uremic patients. Platelet-derived microparticles (PMPs), which are small vesicles with procoagulant activity released from activated platelets, are thought to be involved in clinical thrombogenesis. This study addressed the question of why uremic patients are thrombophilic even though they have a bleeding tendency, focusing on the clinical significance of PMPs.. The subjects were pre-dialyzed patients, patients under hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) therapy, and age-matched healthy controls. Analyses of PMPs were performed using a flow cytometer. Annexin V was used to probe procoagulant activity of PMPs. The impacts of the HD procedure, arteriovenous (AV) fistula, and recombinant human erythropoietin (rHuEPO) treatment on the release of PMPs were additionally assessed.. Major results are: (1) PMP counts were significantly greater in each uremic group than in controls. The PMP counts were not different among three types of uremic groups; (2) PMP counts were significantly higher in uremic patients with thrombotic events than in those without thrombotic events; and (3) the HD procedure and existence of AV fistula did not affect PMP counts, but rHuEPO treatment possibly enhanced the PMP release in these patients.. Elevated PMP counts may trigger thrombosis in uremic patients. The primary cause of PMP elevation in uremia was not clarified in this study.

Topics: Aged; Arteriovenous Shunt, Surgical; Blood Coagulation; Blood Platelets; Erythropoietin; Flow Cytometry; Humans; Middle Aged; Particle Size; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Thrombosis; Uremia

NG-monomethyl-L-arginine (L-NMMA) decreases the expression of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) and increases the expression of GATA-2 mRNA and levels of GATA-2 binding activity, thereby inhibiting erythropoietin (Epo) promoter activity and causing a decrease in the expression of Epo protein. In the present study, we examined the effect of L-arginine on Epo gene expression in Hep3B cells and BDF1 mice.. Hep3B cells were incubated with and without different concentrations of L-NMMA and/or l-arginine. Anemic mice were injected with phosphate-buffered saline (PBS) or L-NAME and L-arginine.. Incubation with L-NMMA under hypoxic conditions inhibited Epo expression, but this inhibition was recovered by the addition of L-arginine. Hypoxia induced the secretions of NO and cGMP, but the addition of L-NMMA inhibited these inductions, though these inhibitions of NO and cGMP by L-NMMA were recovered by the addition of L-arginine. Hep3B cells transfected with the Epo promoter/enhancer-luciferase gene had Epo promoter activity. This activity was inhibited by L-NMMA, but it could be recovered by the addition of L-arginine. L-NMMA induced the binding activity of GATA-2 under hypoxic conditions. This binding activity was inhibited by the addition of L-arginine. The addition of cGMP inhibited L-NMMA-induced GATA-2 binding activity in a dose-dependent manner. The results of an in vivo mouse assay revealed that L-NAME inhibited the expression of Epo, but this inhibition of Epo expression by L-NAME was rescued by pretreatment with L-arginine.. L-arginine rescues decreased erythropoietin gene expression by stimulating GATA-2 with NG-monomethyl-L-arginine.

Topics: Anemia; Animals; Arginine; Cell Hypoxia; Cells, Cultured; Cyclic GMP; DNA-Binding Proteins; Enzyme Inhibitors; Erythropoietin; GATA2 Transcription Factor; Gene Expression; Humans; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; omega-N-Methylarginine; Oxygen; Promoter Regions, Genetic; RNA, Messenger; Transcription Factors; Uremia

Secondary hyperparathyroidism (2-HPT) has an adverse effect on renal anemia and may cause a hyporesponsiveness to recombinant human erythropoietin (rHuEpo) in patients with chronic renal failure. The early effects of parathyroidectomy (PTx) on renal anemia, erythropoietin production, and nutritional state were examined.. Twenty-nine patients under hemodialysis therapy received a PTx for 2-HPT. They were prospectively studied regarding hematological parameters, rHuEpo use, plasma erythropoietin levels, and nutritional condition until 12 months after PTx.. The hemoglobin level showed a significant increase from 3 months after PTx (10.2% +/- 1.5% to 11.2% +/- 1.3%; P <0.01), associated with a consistent increase of the reticulocyte count. These changes lasted until 12 months after PTx. The plasma erythropoietin level showed a gradual increase of up to about 5 times the level of the preoperative value, until 12 months after PTx (22.6 +/- 10.1 to 106.3 +/- 112.1 mU/mL; P <0.001). The weekly dose of rHuEpo administration decreased after 3 months. The serum levels of albumin and total protein also significantly and gradually improved until 12 months after PTx.. PTx caused a significant early improvement in renal anemia in patients with secondary hyperparathyroidism. This effect may be caused by an enhanced erythropoietin production and may also be partially due to the improved nutritional state after PTx.

Topics: Adult; Aged; Drug Resistance; Erythropoietin; Female; Humans; Hyperparathyroidism, Secondary; Linear Models; Male; Middle Aged; Parathyroidectomy; Prospective Studies; Recurrence; Renal Dialysis; Reoperation; Treatment Outcome; Uremia

Chronic renal failure (CRF) is associated with prolonged bleeding time and impaired platelet adhesion and aggregation. Erythropoietin (Epo) administration improves platelet adhesion/aggregation and ameliorates prolongation of bleeding time in CRF. However, the mechanisms of improved platelet function after Epo therapy have not been fully elucidated. The present study examined the hypothesis that the improved uraemic platelet function after Epo therapy is, in part, due to correction of the platelet calcium signalling.. Rats were randomized into four groups after 5/6 nephrectomies to produce CRF. The Epo-treated CRF group received Epo, 150 U/kg, twice weekly for 6 weeks to prevent anaemia; the felodipine and Epo-treated CRF group received Epo but was kept normotensive by felodipine treatment; the placebo-treated CRF group received placebo injections and became anaemic; and the iron-deficient CRF group received Epo but was kept anaemic by dietary iron-deficiency. A group of sham-operated rats was included as normal control. Basal and thrombin-stimulated platelet cytosolic calcium ([Ca(2+)](i)) were determined using a Ca(2+)-sensitive dye (fura-2).. Platelets from placebo-treated CRF group exhibited a profound attenuation of thrombin-stimulated surge in [Ca(2+)](i), which is the final pathway of platelet activation. Long-term Epo administration led to a normalization of the thrombin-induced rise in platelet [Ca(2+)](i) in the CRF animals, independent of either haematocrit or blood pressure values. Further studies revealed that improved Ca(2+) signalling with Epo is associated with increased Ca(2+) uptake and expanded Ca(2+) stores in the platelets.. The defective Ca(2+) signalling in uraemic animals and its improvement with chronic Epo therapy provides the biochemical basis of the previously reported platelet dysfunction and prolonged bleeding time in uraemic patients and animals, and their amelioration with chronic Epo therapy.

Topics: Animals; Blood Pressure; Calcium; Calcium Signaling; Creatinine; Cytosol; Epoetin Alfa; Erythropoietin; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Male; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Uremia

Topics: Administration, Cutaneous; Aged; Angiodysplasia; Erythropoietin; Estradiol; Estrogen Replacement Therapy; Female; Gastrointestinal Hemorrhage; Hepatitis C, Chronic; Humans; Kidney Transplantation; Melena; Recombinant Proteins; Recurrence; Renal Dialysis; Uremia

Topics: Anemia; Carnitine; Drug Resistance; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

Topics: Anemia; Cardiovascular System; Erythropoietin; Heart Diseases; Humans; Uremia; Vascular Resistance

The anemia associated with chronic renal failure is one of the best target diseases for erythropoietin (Epo) gene transfer. We previously reported a short-term (1 month) study of continuous rat Epo delivery by muscle-targeted gene transfer of plasmid DNA expressing rat Epo (pCAGGS-Epo) using in vivo electroporation in normal rats. Here, we performed a long-term pharmacokinetic study of continuous Epo delivery by this method in normal rats and uremic five-sixths nephrectomized rats. In normal rats, Epo gene expression and sufficient erythropoiesis occurred with Epo gene transfer in a dose-dependent manner, and persisted for at least 11 weeks. Repeated administration of the plasmid DNA effectively produced erythropoiesis. Similar erythropoiesis was observed in the uremic rats, and persisted for more than 15 weeks. Both normal and uremic rats showed a significant decrease in platelet count. Moreover, the uremic rats showed Epo-induced hypertension, which is the major side-effect of recombinant human Epo. These results demonstrate that muscle-targeted pCAGGS-Epo transfer by in vivo electroporation is a useful procedure for the long-term continuous delivery of Epo in both normal and uremic rats.

Topics: Animals; DNA; Electroporation; Erythrocytes; Erythropoietin; Genetic Therapy; Hypertension, Renal; Kidney Failure, Chronic; Linear Models; Models, Animal; Muscle, Skeletal; Rats; Uremia

It has been suggested that calcitriol (C) could improve anemia in chronic renal failure. However it remains debatable whether vitamin D has a specific effect on erythropoiesis, or it acts via suppression of hyperparathyroidism.. We enrolled 29 patients with chronic renal failure, free from malignancies, iron deficiency or other chronic or hematological diseases. Aluminium accumulation was also excluded by DFO test. 22 were on hemodialysis and 7 on conservative management, creatinine clearance ranging 22-48 ml/min. Their mean age was 62+/-28 years and duration of renal disease was 98+/-51 months. No patient under-went rHu-Epo or Vitamin D treatment. 4 subjects were enrolled as controls. Samples of peripheral blood were drawn for the Burst Forming Unit-Erythroid (BFU-E) assay. After isolation of mononuclear cells by density gradient centrifugation with Fycoll-Hypaque, a 15-day incubation was set up with four different conditions: a) adding standard dose, 3 U/ml, of r-HuEpo (Dompè Biotec), standard colture; b) combined doses of r-HuEpo, 3 U/ml, and C (Abbott), 30 pg; c) standard dose, 3 U/ml, of r-HuEpo and high dose, 300 pg, of C; and lastly d) combined high doses of r-HuEpo, 30 U/ml, and C, 300 pg.. In the b colture (combined low doses) a higher BFU-E proliferation was found vs standard (a) colture (33.2+/-15.5 vs 17.1+/-9.2, p<0.02); interestingly, either in the c and d studies BFU-E showed an even higher proliferation (52.3+/-24 and 86.3+/-37.8 respectively, p<0.01 vs a). No difference was found when evaluating separately preterminal and hemodialysis patients. In control subjects only colture d showed an increased BFU-E proliferation.. C has a direct effect on erythroid precursors proliferation in vitro, acting in a sinergystic manner with rHuEpo. C may be useful as adjuvant therapy for renal anemia.

Topics: Calcitriol; Calcium Channel Agonists; Cell Division; Cells, Cultured; Chronic Disease; Drug Synergism; Erythroid Precursor Cells; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Uremia

The purpose of this study was to evaluate whether levels of sex hormones and sexual function differ in renal failure patients with and without uremia and the effect of treatment with recombinant human erythropoietin (rhuEPO).. Fifteen males with chronic renal failure who were not receiving hemodialysis and 25 male renal failure patients with uremia who were undergoing hemodialysis were enrolled before and after rhuEPO therapy. Fifteen male volunteers matched for age and weight were also studied. Levels of various blood biochemicals were measured in all patients before and 1 week after rhuEPO treatment. Sexual function was also studied in all patients before and 6 months after rhuEPO treatment.. The control group had significantly higher levels of testosterone (6.21 +/- 1.21 ng/ml) and hematocrit (Hct) (43.2 +/- 2.1%) and significantly lower levels of prolactin (5.27 +/- 1.21 ng/ml), follicular-stimulating hormone (FSH) (7.51 +/- 2.36 mIU/ml) and leutinizing hormone (LH) (4.23 +/- 2.10 mIU/ml) than the two patient groups (p < 0.05 for all comparisons). Patients with renal failure only had significantly lower levels of testosterone and Hct (2.54 +/- 0.53 ng/ml and 21.4 +/- 1.4%, respectively) than those with uremia (3.65 +/- 0.52 ng/ml and 24.3 +/- 2.5%, respectively; p < 0.001 for both comparisons). After rhuEPO therapy, the testosterone and Hct levels of the two patient groups did not reach the level of the control subjects (p < 0.05 for both comparisons). Similarly, the levels of prolactin, FSH and LH were significantly higher in both patient groups than those of control subjects after rhuEPO therapy (p < 0.001 for both comparisons). However, after rhuEPO therapy, significant increases in testosterone and Hct levels were found in both patient groups (p < 0.001 for both comparisons). Sexual function was also markedly improved in the hemodialysis patient group. While 20/25 (80%) male hemodialysis patients reported improved sexual function after rhuEPO treatment, only 3/15 (20%) chronic renal failure patients reported improvement.. In patients with advanced uremia, rhuEPO therapy may result in improved gonadotropic hormone levels and sexual function. Good dialysis quality may contribute to the increase in the incidence of patients with better sexual function.

Topics: Erythropoietin; Gonadal Steroid Hormones; Gonadotropins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Sex; Uremia

Advanced glycation end products (AGE), growth factors, and nitric oxide contribute to alterations of the peritoneum during peritoneal dialysis (PD). These mediators are also involved in chronic uremia, a condition associated with increased permeability of serosal membranes. It is unknown whether chronic uremia per se modifies the peritoneum before PD initiation. A rat model of subtotal nephrectomy was used to measure peritoneal permeability after 3, 6, and 9 wk, in parallel with peritoneal nitric oxide synthase (NOS) isoform expression and activity and structural changes. Uremic rats were characterized by a higher peritoneal permeability for small solutes and an increased NOS activity due to the up-regulation of endothelial and neuronal NOS. The permeability changes and increased NOS activities correlated with the degree of renal failure. Focal areas of vascular proliferation and fibrosis were detected in uremic rats, in relation with a transient up-regulation of vascular endothelial growth factor and basic fibroblast growth factor, as well as vascular deposits of the AGE carboxymethyllysine and pentosidine. Correction of anemia with erythropoietin did not prevent the permeability or structural changes in uremic rats. Thus, in this rat model, uremia induces permeability and structural changes in the peritoneum, in parallel with AGE deposits and up-regulation of specific NOS isoforms and growth factors. These data suggest an independent contribution of uremia in the peritoneal changes during PD and offer a paradigm to better understand the modifications of serosal membranes in uremia.

Topics: Anemia; Animals; Chronic Disease; Creatine; Erythropoietin; Growth Substances; Kidney Failure, Chronic; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Peritoneum; Permeability; Rats; Rats, Sprague-Dawley; Reference Values; Urea; Uremia

To assess the effect of concomitant iron and aluminum loads on bone aluminum accumulation and on the response to the deferoxamine test in rats with the same aluminum surcharge, Wistar rats with chronic renal failure were divided into three groups: iron-overloaded rats (N = 6) (intraperitoneal iron); iron-depleted rats (N = 6) (blood withdrawal two to three times per week); control rats (N = 4) (no manipulation). All groups received intraperitoneal aluminum simultaneously. After 6 wk, a deferoxamine challenge test was performed. Thereafter, bone aluminum and iron were measured. The iron-overloaded rats showed higher bone iron content (iron overloaded: 147.7+/-55.4 microg/g; iron depleted: 7.9+/-1.0, and controls 13.3+/-9.9 microg/g, p < 0.010) and lower bone aluminum content (iron overloaded: 14.2+/-4.0 microg/g; iron depleted: 70.9+/-35.1 microg/g; controls: 72.7+/-28.3 microg/g p < 0.005). No differences were found between the iron-depleted and control rats. After the deferoxamine infusion, the iron-depleted rats tended to have higher serum aluminum increments (p = NS) and higher urinary aluminum excretion (p < 0.012, p < 0.020) than control rats despite similar amounts of aluminum in bone of the two groups. Aluminum bone accumulation was minor if iron and aluminum loads were given concomitantly. The iron depletion influenced the results of the deferoxamine challenge test in rats with similar bone aluminum burden.

Topics: Aluminum; Animals; Bone and Bones; Deferoxamine; Erythropoietin; Iron; Male; Rats; Rats, Wistar; Renal Insufficiency; Uremia

Topics: Adult; Erythropoietin; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Renal Dialysis; Selenium; Uremia

So far it is not clear how erythropoietin affects the anticoagulant properties of vascular endothelium in uremia. Since serotonin is also thought to play a role in the pathogenesis of thrombosis, the aim of the study was to evaluate major components of extrinsic coagulation pathway, markers of endothelial cell injury, lipoprotein (a) and peripheral serotonergic mechanisms during rHuEPO therapy in hemodialyzed patients. The study was performed on chronically hemodialyzed patients divided into two groups: with rHuEPO treatment and without rHuEPO therapy in relation to the control group. In uremic patients, thrombomodulin and von Willebrand factor, activity of factor VII, tissue factor pathway inhibitor (TFPI) activity, TFPI and tissue factor (TF) concentrations, lipoprotein (a) level were significantly higher when compared to healthy volunteers. Treatment with rHuEPO resulted in a further significant rise in markers of endothelial cell injury: thrombomodulin and von Willebrand factor and TFPI concentration. Extrinsic coagulation factors: activities of factor VII and X, TFPI activity and TF activity and concentration, lipoprotein (a) and vitronectin remained unchanged during rHuEPO therapy. Platelet serotonin content and whole blood serotonin were significantly lower in uremic patients relative to healthy volunteers and during rHuEPO treatment they increased significantly. Whole blood serotonin reached normal values. Plasma serotonin, significantly elevated in uremia, did not change during rHuEPO therapy. Serotonin uptake by uremic platelets was significantly impaired and remained unaltered during rHuEPO administration. Serotonin release by uremic platelets was also significantly depressed but a significant improvement was observed in rHuEPO-treated patients. Our data suggest that endothelial injury, TF pathway components and peripheral serotonergic system disturbances may predispose to thromboembolic complications and play a role in the pathogenesis of atherosclerosis in uremic patients, particularly treated with rHuEPO. Increase in TFPI may compensate the increase in TF in these patients.

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation; Blood Platelets; Case-Control Studies; Endothelium, Vascular; Erythropoietin; Female; Humans; Lipoproteins; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Serotonin; Thromboplastin; Thrombosis; Uremia

The aim of this study was to evaluate the effect of both uremia itself and hemodialysis (HD) membranes on the induction of apoptosis. Four groups of subjects were evaluated: 21 nondialyzed (Non-D) patients, 10 continuous ambulatory peritoneal dialysis (CAPD) patients, and 53 HD patients who were on hemophan, cuprophan, cellulose acetate, AN69, and polysulfone; control subjects were nine healthy volunteers. Circulating mononuclear cells were obtained before dialysis and cultured for 48 h. Mean percentage of apoptosis was analyzed by a FACScan flow cytometer using Annexin V-FITC. Cell apoptosis was increased in Non-D patients (11.5 +/- 5.5%) compared with control subjects (2.1 +/- 0.7%, P < 0.001) and CAPD patients (7. 0 +/- 5.8%, P < 0.05). In patients on HD with cuprophan, apoptosis was higher than in control subjects and Non-D and CAPD patients. In Non-D patients, apoptosis was inversely correlated with renal creatinine clearance (r = -0.62, P = 0.003). Cell apoptosis was higher in hemophan than the other HD membranes. In seven patients on hemophan, switching to polysulfone resulted in decreased apoptosis (P < 0.01). Mononuclear cell circulation through mini-dialyzers made of different types of membranes (cuprophan, hemophan, cellulose acetate, AN69, and polysulfone) prouced a significant increase in apoptosis. However, there was a marked difference in the percentage of apoptosis induced by these five membranes, being significantly increased in hemophan and cuprohan compared with the other three membranes. Similar results were obtained when whole blood from healthy donors was circulated through the mini-dialyzers, showing that mononuclear cell apoptosis was increased in hemophan and cuprophan compared with polysulfone. In conclusion, uremia and membrane characteristics may independently affect the mononuclear cell apoptosis.

Topics: Adult; Aged; Apoptosis; Cells, Cultured; Cross-Sectional Studies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Leukocytes, Mononuclear; Male; Membranes, Artificial; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Statistics, Nonparametric; Uremia

Topics: Erythropoietin; Female; Heart Valve Prosthesis; Hemolysis; Humans; Middle Aged; Mitral Valve Stenosis; Uremia

Topics: Aged; Anemia; Biocompatible Materials; Biological Factors; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Erythropoiesis; Erythropoietin; Female; Hemodialysis Solutions; Humans; Male; Membranes, Artificial; Middle Aged; Molecular Weight; Peptide Fragments; Permeability; Polymethyl Methacrylate; Renal Dialysis; Uremia

Topics: Aged; Costs and Cost Analysis; Drug Administration Schedule; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Bacteremia; Erythropoietin; Hemolysis; Humans; Renal Dialysis; Uremia

Patients on regular hemodialysis treatment may develop megaloblastic anemia caused by folate deficiency, but whether folate supplementation is required is still controversial, particularly during erythropoietin administration. Erythrocyte folate concentration is a better indicator of folate status than serum folate, although the latter is the variable generally measured. We measured serum and erythrocyte folate in blood samples from 112 regular hemodialysis patients (57 men, 55 women, 50 treated with erythropoietin, and 62 not) by Stratus Folate immunoenzymatic assay (Dade). Patients with very low serum (<2.87 ng/mL) but normal erythrocyte folate were reinvestigated 4 months later without receiving folate supplementation meanwhile. Serum folate concentrations were 0.48 to 12.76 ng/mL (median, 3.40) and erythrocyte folate 0.19 to 1.85 microg/mL (median, 0.42). Only 37% serum folate values were in the relevant reference interval compared with 80.2% erythrocyte folate values (3.08 to 17.65 ng/mL and 0.24 to 0.64 microg/mL, respectively). A significant correlation was found between serum and erythrocyte folate concentrations, without clinical relevance caused by the wide scatter around the regression line. Serum and erythrocyte folate did not vary significantly between patients given erythropoietin and those not so treated. The folate status of the 24 patients with very low serum folate was almost unchanged 4 months later. According to the serum folate test, 63% of patients needed folate supplementation, whereas the erythrocyte folate test, a better indicator of folate status, suggested that only 1.8% of patients needed folate supplementation. Erythropoietin therapy appears not to be an indication for standard folate supplementation in hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Edetic Acid; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Folic Acid; Folic Acid Deficiency; Hematologic Tests; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Reproducibility of Results; Uremia

Topics: Anemia; Brain; Cognition; Erythropoietin; Event-Related Potentials, P300; Hematocrit; Humans; Recombinant Proteins; Uremia

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Recombinant Proteins; Uremia

We reported in previous studies that plasma triglyceride levels, as well as remnant-like particles-cholesterol (RLP-C) and -triglyceride (RLP-TG) levels, were significantly lower in maintenance hemodialysis (HD) patients treated with erythropoietin (EPO) than in HD patients treated without EPO. However, little is known about the mechanisms underlying the improvements in abnormal RLP metabolism in HD patients. This study investigates whether EPO supplement therapy in cases of uremic anemia increases the plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) levels in HD patients.. Twenty HD patients who had not previously received EPO were divided into two groups according to the stage of HD: 12 at the initial stage, defined as a mean HD duration of 0.35 +/- 0.68 months (range of 0 to 2.47 months), and 8 at the maintenance stage, defined as a mean HD duration of 114.1 +/- 91.9 months (range of 13.0 to 253.9 months). Fasting plasma was collected from the HD patients prior to the start of the EPO supplement therapy and at one month after the therapy. RLP-C levels were determined using a RLP-C JIMRO II kit. Fasting plasma was also collected from the HD patients 10 minutes after an intravenous injection of heparin (30 U/kg body wt). Plasma LPL levels were determined using an enzyme immunoassay, and HTGL levels were determined using a modified version of the Hernell et al method.. Plasma RLP-C levels showed a tendency to decrease after the start of the EPO supplement therapy in HD patients at the maintenance stage. Plasma LPL levels were significantly higher in the two groups of HD patients one month after the start of the EPO supplement therapy than in the same patients prior to the start of the EPO supplement therapy. Plasma HTGL levels were significantly higher in HD patients at the maintenance stage one month after the start of the EPO supplement therapy than in HD patients at the maintenance stage prior to the start of the EPO supplement therapy.. The results of this study suggest that the EPO supplement therapy may reduce plasma RLP-C levels by increasing the plasma LPL and HTGL levels in maintenance-stage HD patients.

Topics: Adult; Aged; Anemia; Apolipoproteins; Cholesterol; Erythropoietin; Female; Humans; Lipase; Lipoprotein Lipase; Lipoproteins; Liver; Male; Middle Aged; Renal Dialysis; Triglycerides; Uremia

To study possible correction of bone disorders (osteopenia, Ca/P-imbalance, bone pain, limited volume of indolent movements) which are still a serious complication associated with renal diseases and pathogenic therapy (steroids).. The bone disorders were treated in 10 uremic hemodialyzed patients (8 men, 2 women; group 1) with vitamin D3 (calcitriol made in Russia) + rhEPO (recormon; Boehringer Mannheim), in 15 patients (15 women, 0 men) with lupus-nephritis (group 2) with vitamin D3 (n = 5, group 2a) or miscalcic (Sandoz) (n = 10, group 2b), in 2 patients (2 men, 0 women) with glomerulonephritis (group 3) with vitamin D3 + miacalcic. Additionally all the patients received Ca salts. In groups 2 and 3 renal function was normal. The duration of the treatment was 3-6 months.. In all the groups we obtained an analgetic effect (attenuation of bone pain and more indolent movements), improvement of life quality, diminished need in analgetics, elevation of serum Ca level (p > 0.05).. Treatment of renal patients with bone affection with vitamin D3 and miacalcic has an analgetic effect, improves life quality.

Topics: Adult; Analgesics; Bone Diseases; Calcitonin; Calcium; Cholecalciferol; Drug Therapy, Combination; Erythropoietin; Female; Glomerulonephritis; Humans; Lupus Nephritis; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Uremia

Erythropoietin has shown to be effective in the correction of the hemostatic defect present in uremic patients. We have investigated the possible effect of recombinant human erythropoietin (rHuEPO) on the signaling processes occurring in platelets. Platelet suspensions were obtained from hemodialyzed patients before and after at least one month of initiating treatment with rHuEPO. Aliquots of non-activated or thrombin-activated platelets were treated to obtain platelet lysates or processed to extract platelet cytoskeleton. Samples were resolved by 8% SDS-polyacrylamide gel electrophoresis followed by Western blotting. After thrombin activation, proteins p120, p85, p78, p75, pp62, pp60, p59, p58, p56, p54 and p52 associated with the Triton-insoluble cytoskeletal fraction appeared phosphorylated in control profiles. In profiles from platelets obtained from uremic patients before treatment with rHuEPO, only proteins p58 and p56 appeared clearly and p54 was slightly phosphorylated. However, in platelets from the same patients under rHuEPO treatment, thrombin-induced phosphorylation improved to levels even above those observed in control profiles. Specially, the band at 54KDa appeared consistently more phosphorylated in all the patients under rHuEPO treatment. Although it is accepted that part of the hemostatic effect of erythropoietin is mediated by an increase in hematocrit, our study suggests that it enhances platelet signaling in uremic platelets which may explain the improvement of platelet response to activating stimulus before clinically noticeable elevation of hematocrit.

Topics: Aged; Blood Platelets; Erythropoietin; Female; Humans; Male; Middle Aged; Phosphorylation; Signal Transduction; Tyrosine; Uremia

Topics: Anemia; Animals; Carnitine; Erythropoietin; Hematocrit; Male; Rats; Rats, Wistar; Recombinant Proteins; Uremia

This study investigated potential reasons why erythropoietin (EPO) given therapeutically to patients with renal failure may increase peripheral, but not renal, vascular resistance. This was done by comparing the effects of EPO on resting tension in normal renal interlobular and subcutaneous vessels from uraemic patients. In human subcutaneous arteries from uraemic subjects, noradrenaline- and KCl-induced vasoconstrictions were enhanced when nitric oxide (NO) production was blocked with N(G)-nitro-L-arginine methyl ester (L-NAME), but were unaffected by EPO, while acetylcholine- and bradykinin-induced concentration-dependent relaxations were markedly attenuated by L-NAME, but not by EPO. The noradrenaline- and KCl-induced vasoconstrictions of human renal interlobular arteries were unaffected by the presence of L-NAME, but were attenuated by EPO (20 units.ml(-1)) by some 33% (P<0.01); this effect was enhanced by the co-administration of L-NAME. Acetylcholine and bradykinin caused comparable dilatations of the interlobular arteries; the response to the former was attenuated by L-NAME, but none of these responses were changed by EPO. EPO given alone, at a concentration of either 0.1 or 20 units.ml(-1), had no effect on basal resting tone. NO production mediated both acetylcholine- and bradykinin-induced relaxation in this vessel type. In contrast, in the interlobular arteries there was no indication of NO modulating the level of vasoconstriction, and it only mediated acetylcholine-induced dilation. These acute responses to EPO only partially explain its differential effects on the vasculature in renal failure.

Topics: Acetylcholine; Adolescent; Adult; Aged; Aged, 80 and over; Arteries; Bradykinin; Child; Child, Preschool; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Inhibitors; Erythropoietin; Female; Humans; Infant; Male; Middle Aged; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; Potassium Chloride; Renal Artery; Skin; Uremia; Vascular Resistance; Vasoconstriction; Vasodilator Agents

Hemodialysis is a method of treatment of patients suffering from terminal renal disease and consists in removing uremic toxins from blood. The influence of hemodialysis on rheological properties of red blood cells was ascertained. We studied the deformability of RBC after density gradient separation of whole blood drawn from patients with renal disease before and after dialysis. The improvement in deformability of cells from the top layers was observed in postdialysis samples.

Topics: Anemia; Cell Size; Centrifugation, Density Gradient; Erythrocyte Deformability; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Reticulocytes; Uremia

Two patients with non-insulin-dependent diabetes mellitus (NIDDM) and moderate chronic renal failure experienced a worsening of glycaemic control when recombinant human erythropoietin (r-HuEPO) was introduced, leading to insulin therapy. A 71-year-old woman with a 20-year history of NIDDM had presented histologically documented diabetic nephropathy for 2 years during which glucose control was stabilized by a diet and glibenclamide 10 mg. In the 6 months following introduction of r-HuEPO, hyperglycaemic symptoms developed, and HbA1C increased from 8.9% to 12.3%. During this period, no intercurrent events occurred, except epistaxis due to accelerated hypertension one month after r-HuEPO was started. A 62-year-old man had a 15-year history of NIDDM, with proliferative retinopathy, macroproteinuria and chronic renal failure for 4 years. The day after the first injection of r-HuEPO, capillary glucose level rose dramatically. In both of these cases, antihypertensive treatment was increased and insulin introduced. The role of r-HuEPO in hyperglycaemia was probable in the first case and highly probable in the second. Reports about the effects of r-HuEPO on glucose metabolism in uraemic patients are conflicting. Short- and long-term effects can differ, although long-term benefit is likely. The fact that our patients were not dialized may have been important. Clinicians should be aware that glucose control may deteriorate with r-HuEPO, requiring some uraemic NIDDM patients to undergo insulin therapy.

Topics: Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erythropoietin; Female; Humans; Insulin; Male; Middle Aged; Recombinant Proteins; Uremia

Topics: Adolescent; Anemia, Aplastic; Delayed-Action Preparations; Erythropoietin; Ferrous Compounds; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Parvoviridae Infections; Parvovirus B19, Human; Renal Dialysis; Uremia

In patients with chronic renal failure, rHuEpo therapy ameliorates anaemia and improves wellbeing, exercise tolerance, and appetite. Both leptin and neuropeptide Y play an important role in regulation of appetite and energy balance in humans.. The present study aimed to assess the influence of 12 months rHuEpo therapy on plasma leptin and neuropeptide Y concentrations in 15 haemodialysed patients (HDP) (6F, 9M; mean age 40.8+/-2.9 years; mean BMI 23.6+/-1.1 kg/m2; mean duration of HD 3.3+/-0.6 months) (Epo group). A second group (No-Epo group) consisted of 17 HDP (9F, 8M; mean age 44+/-3.2 years; mean BMI 24.3+/-1.0 kg/m2; mean duration of HD 2.5+/-0.4 months) not treated with rHuEpo for 12 months. Basal plasma leptin and neuropeptide Y concentrations were estimated by RIA at the beginning and after 3, 6, 9 and 12 months of rHuEpo therapy (Epo group) or clinical observation (No-Epo group). The control group consisted of 30 healthy subjects (15 females, 15 males, mean age=38.2+/-1.7 years, mean BMI 24.5+/-0.7 kg/m2).. Baseline plasma leptin concentrations in HDP were higher, although statistically not significant than leptinaemia in healthy subjects. After 3, 6, and 12 months of rHuEpo therapy plasma leptin concentrations were significantly lower than at the beginning of the study. Baseline plasma neuropeptide Y concentrations in HDP did not differ significantly from controls. After 3 and 6 months of the study period plasma neuropeptide Y concentrations increased significantly in patients of both the Epo and No-Epo group. This increase was, however, significantly higher in rHuEpo-treated than in untreated patients.. (1) rHuEpo treatment in haemodialysed patients with chronic renal failure is followed by a significant decline of leptinaemia and disappearance of the physiological positive BMI/leptinaemia relationship. (2) Suppression of leptinaemia induced by rHuEpo may be of clinical relevance in haemodialysed patients with chronic renal failure.

Topics: Adult; Body Mass Index; Erythropoietin; Female; Humans; Leptin; Male; Neuropeptide Y; Osmolar Concentration; Proteins; Recombinant Proteins; Reference Values; Renal Dialysis; Time Factors; Uremia

The aim of this study was to compare clinical and biological results in 4 standard hemodialyzed patients originally treated by three 4-5 h sessions per week and converted within one year to daily hemodialysis sessions of 2-2.5 h each 6 times per week. The modalities and the total weekly dialysis times remained the same. With daily hemodialysis, the blood pressure and left ventricular mass index decreased significantly (p < 0.01). A significant decrease in the urea time averaged deviation (TAD) (p < 0.005) and increase in the Kt/V index (p < 0.05) were observed. A gain in dry weight was shown with a rise in caloric intake from 33+/-3.21 to 40.8+/-6.35 kcal/kg/day (p < 0.05), and the normalized protein catabolic rate (nPCR) increased significantly (p < 0.0038). One patient who was receiving erythropoietin (EPO) for anemia could stop his treatment. No arteriovenous fistula complications were observed. Daily hemodialysis seems to be the method of choice to manage hypertension and left ventricular hypertrophy in uremic patients. The increase of the urea TAD to a value closer to that of the healthy kidney due to the increase of the frequency of dialysis is probably the main explanation for clinical improvement.

Topics: Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Pressure; Energy Intake; Erythropoietin; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Proteins; Renal Dialysis; Time Factors; Ultrasonography; Urea; Uremia; Weight Gain

Topics: Cardiac Output; Erythropoietin; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Parathyroid Hormone; Renal Dialysis; Uremia

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Recombinant Proteins; Risk Factors; Uremia

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.

Topics: Animals; Blood Pressure; Creatinine; Endothelin-1; Erythropoietin; Hematocrit; Humans; Hypertension; Male; Rats; Rats, Wistar; Recombinant Proteins; Uremia

The concentrations of bcl-2 protein that can block programmed cellular death in various cell lines were evaluated in blood samples from 10 uremic patients on hemodialysis, 10 uremics not yet on hemodialysis, and in 10 healthy controls. The bcl-2 protein variations (in uremics on dialysis) were ascertained in patients during the dialysis session. Oxidative stress was evaluated in all groups by assaying the products of intraerythrocytic lipoperoxidation. Dialyzed and nondialyzed uremic patients had higher bcl-2 protein concentrations than healthy subjects. Dialysis causes a significant reduction in the concentrations of bcl-2 protein which becomes statistically significant during the 3rd hour. In both groups of uremic patients a positive correlation was found between bcl-2 protein and products of lipoperoxidation.

Topics: Aged; Apoptosis; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Leukocyte Count; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Renal Dialysis; Uremia

The potential stimulating effect of erythropoietin on the production of fetal proteins (FPs) has not been explored in human subjects. Therefore, the plasma levels of fetal fibrinogen (FF), carcinoembriogenic antigen (CEA), alpha-fetoprotein (AFP), and fetal hemoglobin (HbF) were measured in 12 uremic hemodialyzed patients before the first administration and after 1, 2, and 3 months of low-dose erythropoietin (r-Hu-EPO; 45 U/kg body wt I.V., thrice weekly). Such a treatment efficaciously increased total hemoglobin (Hb). CEA and AFP increased from 5.8 +/- 1.1 ng/ml and 2.9 +/- 0.9 ng/ml to the final value of 43.2 +/- 3.9 ng/ml and 8.7 +/- 1.1 ng/ml, respectively, in the absence of detectable neoplastic diseases. The levels of FF did not change. HbF levels increased from <3% of Hb to the peak value of 48% at the end of the first month; subsequently, a progressive reduction in HbF was observed. Similar changes were detected in the reticulocyte count (RET). A striking correlation was found between HbF and RET (r = 0.8633, p < 0.0001), indicating that the increment in HbF was dependent on the erythroid activity. In conclusion, this study evidences broader than expected effects of erythropoietin on the synthesis of FP and suggests that (1) r-Hu-EPO markedly increases HbF in a condition of suppressed bone marrow activity, (2) the measurement of the cell proliferation markers CEA and AFP is unreliable during r-Hu-EPO therapy, and (3) the prothrombotic state associated with chronic r-Hu-EPO treatment in patients with uremia cannot be attributed to the presence of FF.

Topics: Adult; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Fetal Hemoglobin; Fetal Proteins; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Reticulocyte Count; Time Factors; Uremia

To investigate the role of uremia in the development of human recombinant erythropoietin (r-HuEPO)-induced hypertension, Wistar rats were divided into a uremic (subtotal nephrectomy) and a control group. After three weeks, both groups were again divided and each subgroup received either r-HuEPO (100 u/kg s.c., 3 times weekly) or the vehicle for a further 3 weeks. Hematocrit, blood pressure and blood chemistry were measured prior to surgery, before either vehicle or r-HuEPO treatment and before euthanasia. The uremic group developed anemia, hypertension and all the biochemical features observed in humans with end-stage renal disease. r-HuEPO therapy increased hematocrit from 29 +/- 2.5% to 46 +/- 2% (p < 0.01) in the uremic rats. The mean baseline blood pressure was 119 +/- 10 mmHg. At week 3, mean blood pressure was unchanged in control rats, but it was increased to 151 +/- 5 mmHg (p < 0.01) in the nephrectomized group. At week 6, mean blood pressure in the untreated uremic rats remained unchanged from week 3, but blood pressure in the uremic animals treated with r-HuEPO increased significantly to 187 +/- 8 mmHg (p < 0.01). There was no significant correlation between hematocrit and blood pressure in the r-HuEPO treated uremic group (r = 0.01, NS). r-HuEPO had no effect on blood pressure in control rats despite a significant increase in hematocrit. These results indicate that the blood pressure response to r-HuEPO is enhanced in rats with chronic renal failure.

Topics: Animals; Blood Pressure; Creatinine; Erythropoietin; Hematocrit; Humans; Male; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Reference Values; Systole; Uremia

Topics: Antigens, CD; Blood Platelets; Cold Temperature; Erythropoietin; Estrogens; Fibrinogen; Hemorrhage; Humans; Injections, Intravenous; Integrin beta3; Integrins; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Renal Dialysis; Uremia; von Willebrand Factor

Topics: Anemia; Drug Resistance; Echocardiography; Erythropoietin; Humans; Male; Middle Aged; Pericardial Effusion; Pericarditis; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Aged; Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Uremia

Anemia in chronic renal failure is predominantly caused by diminished erythropoietin synthesis by diseased kidneys. While iron deficiency is often stated as a cause of anemia in chronic renal failure prior to end-stage renal disease, its relative contribution is debated. It is speculated that rather than frank 'iron deficiency', many patients with chronic renal failure may indeed have impaired utilization of iron. We analyzed 139 consecutive patients with chronic renal failure starting maintenance hemodialysis to determine the relationship between hematocrit, measures of renal function (blood urea nitrogen and serum creatinine concentration), and measures of iron availability (serum transferrin saturation, serum iron level and serum ferritin). The 139 study subjects (60 men, 79 women) comprised 116 blacks (83%), 15 hispanics (11%), and 8 whites (6%) of a mean age 56 +/- 15 years. Only 23 (17%) of 139 subjects had positive hemoccult stool test for blood. Their mean hematocrit was 24 +/- 4.5%, mean blood urea nitrogen concentration was 121 +/- 38, mean serum creatinine concentration was 12.6 +/- 5.2 mg/dl, mean serum transferrin saturation was 22 +/- 14%, mean serum ferritin level was 235 +/- 194 U/l, mean serum iron level was 55 +/- 40 U/l, and mean total iron binding capacity was 254 +/- 93%. Multiple regression analysis with hematocrit as the outcome variable, and blood urea nitrogen level, serum creatinine concentration, serum albumin concentration, serum transferrin saturation, and serum ferritin level as the independent variables, showed an inverse correlation between hematocrit and serum creatinine concentration (p = 0.002). We conclude that in patients with chronic renal failure starting uremia therapy, anemia does not correlate with any of the commonly measured indices of body iron stores. We infer that impaired utilization of iron may be a significant factor in the anemia of chronic renal failure.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Urea Nitrogen; Creatinine; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Renal Dialysis; Serum Albumin; Transferrin; Uremia

Topics: Anemia, Iron-Deficiency; Cytokines; Erythropoietin; Ferric Compounds; Ferritins; Humans; Iron; Renal Dialysis; Uremia

Topics: Blood Pressure; Erythropoietin; Humans; Hypertension; Plasma Volume; Platelet Aggregation Inhibitors; Uremia

The influence of r-HuEPO on the activity of erythrocyte transketolase (ETKA), glutathione reductase (GSH) and glutamic-pyruvic transaminase (EGPT) was determined by spectrophotometry. 150 IU/kg BW/week of r-HuEPO was given i.v. during 2 months to 12 predialyzed uremics (PDU). Twenty healthy volunteers (HV) served as controls. GSH and EGPT activity were expressed as a coefficient. ETKA in HV = 2.39 +/- 0.10 and PDU = 1.53 +/- 0.10 mumol/ml/min differed significantly (p < 0.001). GSH in HV = 1.20 +/- 0.09 and PDU = 1.25 +/- 0.07, EGPT in HV = 1.20 +/- 0.10 and PDU = 1.38 +/- 0.11 differed significantly (p < 0.01 and p < 0.001, respectively). After 2 months of r-HuEPO treatment, ETKA, GSH and EGPT rose significantly (p < 0.01). Thus, r-HuEPO increases the activity of enzymes related with the content of vitamins B1, B2 and B6 in uremics.

Topics: Alanine Transaminase; Creatinine; Erythrocytes; Erythropoietin; Glutathione Reductase; Hematocrit; Humans; Recombinant Proteins; Reference Values; Renal Dialysis; Transketolase; Uremia

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.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythrocytes; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Heme; Hemoglobins; Humans; Hydroxymethylbilane Synthase; Male; Middle Aged; Porphobilinogen Synthase; Porphyrins; Recombinant Proteins; Renal Dialysis; Uremia; Zinc

The mechanism of erythropoietin-induced hypertension in dialysis patients is unclear. Intracellular calcium ([Ca2+]i) may be altered in both hypertension and uraemia, and the effects of both uraemia and r-HuEPO on vascular smooth muscle [Ca2+]i and blood pressure (BP) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were therefore studied. Male WKY and SHR underwent partial nephrectomy or sham operation. Three weeks later a 28-day period of treatment with either r-HuEPO 100 U/kg, s.c., 3 times/week or buffer was commenced (n = 10-12 for each subgroup). BP was measured weekly, by noninvasive Doppler tail-cuff assessment. [Ca2+]i was measured following loading with fura-2 in pooled, primary aortic vascular smooth muscle cells (VSMC). Serum urea and creatinine rose 3- to 4-fold after partial nephrectomy. Treatment with r-HuEPO did not change renal function further in either uraemic or control WKY or SHR. Haemoglobin increased in both non-uraemic WKY (16.2-20.3 g/dl) and SHR (16.4-20.5 g/dl) and uraemic animals (WKY 13.9-20.9; SHR 13.8-18.8 g/dl; p < 0.01 for all changes) following 4 weeks of r-HuEPO treatment. BP was unaffected by r-HuEPO in WKY but increased in nonuraemic SHR (210-250; p < 0.01) and in uraemic SHR (224-251 mm Hg; p < 0.001) at 4 weeks. VSMC [Ca2+]i was higher in SHR than WKY (121 vs. 83 nmol/l; MANOVA p < 0.05) but no effect of uraemia or r-HuEPO on [Ca2+]i was detected. In conclusion, the hypertensive effects of r-HuEPO are augmented both in a genetic model of hypertension and in uraemia. Although VSMC [Ca2+]i was elevated in SHR, the further increase in BP induced by r-HuEPO was not associated with alterations in VSMC cytosolic calcium.

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Blood Pressure; Calcium; Creatinine; Cytosol; Erythropoietin; Hemoglobins; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Nephrectomy; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins; Urea; Uremia

Uremic patients undergoing hemodialysis (HD) are known to be highly susceptible to infections. Recent data indicate that in addition to its well-known stimulating effects on red cell production, erythropoietin (EPO) may also have immunomodulating properties. The aim of this study was to examine the effect of EPO on lectin-induced T-lymphocyte transformation in uremic patients, as part of its effect on the immune response. Sixteen HD patients and 20 age- and sex-matched healthy controls were compared before and after 6 and 20 weeks of EPO treatment. T lymphocytes were analyzed for their mitogenic activity following treatment with phytohemagglutinin (PHA), concanavalin A (CON A) and anti-CD3 by measuring 3H-thymidine incorporation. HD patients showed reduced mitogenic responses to all mitogens tested, compared to healthy controls. During the 6 weeks of EPO administration, a significant increase in T-lymphocyte activity could be demonstrated following exposure to all three mitogens (PHA, from 32 +/- 2 to 45 +/- 8; CON A, from 11 +/- 3 to 25 +/- 9; anti-CD3, from 11 +/- 3 to 22 +/- 5, means +/- SD). This increase was augmented after 5 months of EPO treatment. We conclude therefore that EPO improves in vitro T-cell mitogenic proliferation, even after short periods of treatment.

Topics: Adjuvants, Immunologic; Cell Division; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mitogens; Renal Dialysis; T-Lymphocytes; Thymidine; Transformation, Genetic; Uremia

Erythropoietin treatment is known to correct anemia and to improve hemostasis. Since platelets may contribute to thromboembolic complications, we assessed platelet aggregation in whole blood and platelet-rich plasma from chronically hemodialyzed patients treated with erythropoietin and evaluated in vitro effects of this drug on aggregatory responses of uremic and normal platelets. Recombinant human erythropoietin was given to uremic patients at a dose of 2,000 IU subcutaneously three times a week. Platelet aggregation in whole blood and platelet-rich plasma was induced by collagen, ADP, arachidonic acid, and ristocetin. In uremic patients, erythropoietin therapy resulted in an enhancement of platelet sensitivity to various agonists, particularly in platelet-rich plasma, reaching values comparable to those of healthy volunteers. In vitro studies we were unable to show any direct effect of erythropoietin, used at concentrations that occurred post intravenous administration, on platelet aggregation both in whole blood and in platelet-rich plasma.

Topics: Adenosine Diphosphate; Adult; Aged; Anemia; Arachidonic Acid; Case-Control Studies; Collagen; Erythropoietin; Hemostasis; Humans; In Vitro Techniques; Middle Aged; Platelet Aggregation; Recombinant Proteins; Renal Dialysis; Ristocetin; Uremia

Ten patients (18 +/- 1 yr) on chronic hemodialysis (HD) with anemia were studied before and after treatment with erythropoietin (EPO) for 9 mo. Six patients had evidence of iron overload (serum ferritin over 300 ng/ml; group I) and the other four patients (serum ferritin below 300 ng/ml; group II) did not. Before treatment, both groups of patients were glucose tolerant but insulin resistant and hyperinsulinemic. There was equal correction of anemia but no significant changes in serum biochemistry (apart from iron studies) or anthropometric measurements in both groups. With amelioration of anemia and iron overload in group I, insulin sensitivity increased by 53% to within normal values. Insulin secretion also normalized. With amelioration of anemia but no change in iron status in group II, insulin sensitivity (increased by 60%) and insulin secretion also normalized. Thus correction of anemia by EPO reversed insulin resistance and hyperinsulinemia in HD patients with or without iron overload. The effects of correction of anemia rather than iron overload may be more important in the pathogenesis of insulin abnormalities in end-stage renal disease.

Topics: Adolescent; Adult; Anemia; Erythropoietin; Ferritins; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin Resistance; Kidney Failure, Chronic; Renal Dialysis; Uremia

Anemia due to decreased erythropoietin production is one of the major complications in uremic patients. The aim of the study is to evaluate the clinical efficiency and safety of rHuEPO in the treatment of anemia in uremic children receiving regular hemodialysis. Three uremic children, age 8, 12, and 14 year-old, under maintenance hemodialysis with hematocrit (Hct) value lower than 20% were observed for 6 months. rHuEPO 50 u/kg were given intravenously three times a week initially. Hct value of 30% was the target of therapy. All 3 children responded to the therapy and reached the target Hct value within 11 to 18 weeks. They received no further transfusion after the therapy. The maintenance dose to keep Hct value around 30% is 75 to 120 u/kg/wk. The serum biochemistry examination showed no difference before and after the therapy. The physical endurance, body weight and height increased in all children. The left ventricular end-diastolic dimension in echocardiography decreased and the ejection fraction increased after 6 months of the treatment. Serum ferritin concentrations decreased in all children. Mild hypertension developed in one child. Heparin dose was increased when the target Hct value was around 30% in 2 children. We suggested that low dose rHuEPO therapy was safe and effective in uremic children, but close monitoring for the development of hypertension and iron deficiency was mandatory.

Topics: Adolescent; Anemia; Child; Erythropoietin; Humans; Recombinant Proteins; Uremia

A Before-after study based on self-comparison was conducted to assess the early efficacy of recombinant human erythropoietin (r-HuEPO) in 51 patients with uremic anemia who were subjected to dialyses. A significant elevation of levels of Hb and Hct was observed (P < 0.001, P < 0.005) after r-HuEPO therapy. And hemorheologic tests showed whole blood viscosity was obviously increased (P < 0.005), but no changes in plasmic viscosity and platelet adhesion rate were found (P > 0.05). No increase of blood pressure of the patients was noticed in the early period after treatment. The results revealed a satisfactory early efficacy with few sideeffects of the r-HuEPO treatment in uremic anemia.

Topics: Adult; Anemia; Blood Viscosity; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Topics: Adult; Anemia; Blood Coagulation; Blood Coagulation Tests; Case-Control Studies; Drug Monitoring; Erythropoietin; Humans; Ketanserin; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Renal Dialysis; Thrombosis; Uremia

Topics: Acetates; Erythropoietin; Fetal Hemoglobin; Humans; Recombinant Proteins; Renal Dialysis; Uremia

Endogenous erythropoietin (EPO) secretion can still be modulated in patients with end-stage renal failure but only in response to strong stimuli. Thus even anephric dialysis patients are able to increase EPO production acutely when exposed to a marked hypoxic stimulus. The present study was designed to test the hypothesis that a decrease of plasma calcium or the administration of various antihypertensive agents might be able to induce acute changes of plasma EPO concentration. Four groups of chronic hemodialysis patients were studied. Eight patients volunteered for the induction of an acute, transient hypocalcemia via a calcium-free dialysate during the initial 60 min of a regular dialysis session of 240 min. Plasma immunoreactive (i) EPO, total calcium, and intact parathyroid hormone (iPTH1-84), as well as blood ionized calcium and blood gases were measured before as well as 30, 60, 120 and 240 min after the start of dialysis. In addition, plasma iEPO was measured 48 h after the session. Patients of group 2 (n = 6), group 3 (n = 6), and group 4 (n = 7) received the day after a hemodialysis session a single dose of either acetazolamide, furosemide, or enalapril, respectively, and their plasma iEPO was determined before and 3, 6 and/or 24 h after drug administration. In group 1, plasma total calcium decreased from 2.39 +/- 0.07 mM (mean +/- SEM) to 1.98 +/- 0.02 and 1.83 +/- 0.03 mM after 30 and 60 min of dialysis, respectively, and blood ionized calcium from 1.28 +/- 0.04 to 1.02 +/- 0.03 and 0.92 +/- 0.04 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Antihypertensive Agents; Calcium; Chronic Disease; Dialysis Solutions; Erythropoietin; Female; Humans; Hypocalcemia; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Uremia

In 14 chronic uraemic patients on regular haemodialysis treatment mean numbers of fibrinogen (Fg) receptors and glycoprotein IIb (GPIIb) molecules on one blood platelet were 8370 +/- 1282 and 15,694 +/- 2102 respectively, and they were significantly lowered in comparison with those found in 14 healthy persons (37,826 +/- 966 and 57,994 +/- 6824 respectively). A high positive correlation was found between numbers of GPIIb molecules and those of Fg receptors both in chronic uraemic patients and healthy subjects. Four-month treatment of haemodialysis patients with recombinant human erythropoietin (rHuEpo) induced significant rises in haematocrit from 22.3 +/- 1.2 to 31.2 +/- 1.7%, blood platelet count from 164,000 +/- 27,000/microliters to 206,000 +/- 16,000/microliters and mean platelet volume from 7.08 +/- 0.29 fl to 8.26 +/- 0.22 fl. However, in haemodialysis patients numbers of the investigated surface platelet receptors, measured at 8 and 16 week of rHuEpo treatment, remained unchanged.

Topics: Adenosine Diphosphate; Adult; Bleeding Time; Blood Platelets; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Integrin alpha2; Male; Membrane Glycoproteins; Middle Aged; Platelet Activation; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Renal Dialysis; Uremia

In 69 patients on chronic haemodialysis, blood sampled randomly during dialysis was analyzed for carboxyhaemoglobin (COHb). The median value was 1.40% (range 0.9-2.3) in non-smoking patients and (1.4-7.5) in smokers. In non-smokers treated with erythropoietin (EPO) correlation was found between COHb and the weekly EPO dose (r = 0.57, p = 0.007). In smoking patients not given EPO, the COHb correlated well with the number of cigarettes smoked (r = 0.84, p = 0.003). The COHb values did not correlate to the haemoglobin values. It is concluded that COHb levels in uraemic non-smokers are elevated because of increased endogenous CO production from the enhanced erythrocyte turnover. As even low COHb levels may negatively influence the oxygen status of the uraemic patient, the addition of exogenous CO from cigarette smoking should be avoided.

Topics: Adult; Aged; Carbon Monoxide; Chronic Disease; Erythropoietin; Female; Humans; Longitudinal Studies; Male; Middle Aged; Renal Dialysis; Smoking; Uremia

Topics: Acquired Immunodeficiency Syndrome; Aluminum; Anemia; Drug Resistance; Erythropoietin; Humans; Hyperparathyroidism; Iron; Kidney Transplantation; Uremia

It is generally accepted that the anemia of uremia is caused by decreased production of erythropoietin. Nevertheless, the erythropoietin titers are not lower than but equal to or higher than in normal non-anemic individuals. To examine this discrepancy, erythrokinetic studies were made of 22 hematologically stable dialysis patients without clinical or laboratory evidence of extrarenal inflammation, infection, or neoplastic disorders. The red cell life span was normal in 14, and because of stable hematocrits, their daily rate of red cell production had to equal their daily rate of red cell destruction, which could be determined by dividing the red cell mass by red cell life span. These rates were about one half the rates of normal stable individuals, despite the same or higher erythropoietin titers. This suggests that the anemia of uremia is caused in part by a decreased bone marrow response to endogenous erythropoietin.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Kinetics; Uremia

The aim of this study was to investigate the mechanism of erythropoietin-induced hypertension in respect to its action on blood serotonergic system. The experiment was carried out on healthy rats and animals with experimental chronic renal failure. Erythropoietin (rHuEPO) injected into the healthy and uremic rats caused an increase in systolic blood pressure. This effect was completely abolished by ketanserin, an antagonist of 5-HT2 receptors. Concomitantly a rise in blood and platelet serotonin concentration was observed. It is concluded that serotonin may play a role in the development of hypertension caused by rHuEPO. Moreover, ketanserin may serve as a drug for pharmacological protection of rHuEPO-induced rise of blood pressure in uremia.

Topics: Anemia; Animals; Blood Platelets; Endothelium, Vascular; Erythropoietin; Hypertension; Ketanserin; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renin-Angiotensin System; Serotonin; Serotonin Antagonists; Uremia; Vasoconstriction

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Time Factors; Uremia

This paper reports a study on the treatment of predialysis patients with recombinant human erythropoietin (r-HuEPO). The haematocrit, haemoglobin, reticulocyte and platelet values as well as creatinine and creatinine clearance evaluated by standard and radio-isotopic methods before, during and after r-HuEPO treatment were determined. The slope of the inverse creatinine versus time curves was studied too. The authors did not observe any variation of the renal function parameters during and after study and suggest their protocol of r-HuEPO administration for predialysis patients.

Topics: Anemia; Blood Cell Count; Erythropoietin; Female; Hematocrit; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Recombinant Proteins; Uremia

Since 1982, 32 uraemic patients were treated in our institution by high flux haemodiafiltration (H-HDF) in order to shorten significantly the dialytic treatment session. H-HDF used a high surface area filter (1.4-1.9 m2) with high hydraulic permeability (polyacrylonitrile and polysulfone), at high blood flow (450 ml/min) and high rates of reinfusion of substitution fluid (22 l/session). In this way the dialytic session was shortened to 140 +/- 19 min, maintaining a good cardiovascular stability and high dialytic efficiency (Kt/V > 1.1). Human recombinant erythropoietin rHuEpo introduced in the therapy of this group in 1987 has resulted in an improvement of renal anaemia, but also a prolongation of the time of dialytic treatment due to a decrease in the efficiency of filters. During the period of the study, the treatment time increased from 140 +/- 19 min to 168 +/- 25 min with a concomitant increase of haematocrit and haemoglobin (from 24% to 36% and from 7.9 to 10.5 g/dl, respectively). H-HDF maintains a noticeable increase in dialytic efficacy with good cardiovascular stability, but the goal of a significant reduction in the time of treatment can no longer be obtained.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hematocrit; Hemodiafiltration; Humans; Male; Middle Aged; Recombinant Proteins; Time Factors; Uremia

In uremic patients a disturbed lipid metabolism is observed. In our former works a positive effect of erythropoietin (EPO) on blood platelet phospholipids composition in uremic patients was indicated. In this study we examined the EPO influence on blood plasma phospholipids in chronically hemodialyzed patients. Phospholipids were measured by thin layer chromatography method before and 3 months after the beginning of EPO treatment. EPO was administered subcutaneously, 2000 U twice a week. Decreased phosphatidylethanolamine, phosphatidylinositol and phosphatidylcholine levels were shown in patients before EPO treatment, compares with the control group. During EPO therapy the phospholipid levels approached to normal values. Conclusion is that EPO administration has a positive influence on blood plasma phospholipids in hemodialyzed patients. The detailed importance of this event has been not known yet, but our observations suggest that EPO profoundly interferes with lipid metabolism.

Topics: Adult; Drug Administration Schedule; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Phospholipids; Recombinant Proteins; Renal Dialysis; Uremia

The association between the use of erythropoietin and urea or creatinine clearance was studied in two populations on continuous peritoneal dialysis (CPD) residing either at an altitude of 1600 m (n = 194) or at sea level (n = 108). Among peritoneal and total KT/V urea and creatinine clearance (CCr) indices, only total CCr was lower in the high altitude group receiving erythropoietin than in the corresponding group not receiving erythropoietin (68.0 +/- 34.9 vs 82.9 +/- 40.9 L/1.73 m2 weekly, p < 0.01). However, 24-hour urine volume and urinary KT/V urea and CCr were consistently lower in the groups receiving erythropoietin than in those not receiving erythropoietin. Total weekly KT/V urea < or = 1.70 and CCr < or = 52 L/1.73 m2 were considered indicators of inadequate CPD. Although the percent of patients receiving erythropoietin did not differ overall between groups with adequate and those with inadequate CPD, a trend towards more frequent use of erythropoietin was found in the sea level group with inadequate CCr versus the group with adequate CCr (28.2% vs 16.9%, p = 0.084). In CPD decreased renal function is associated with more frequent use of erythropoietin. Whether inadequate total urea or creatinine clearance is also associated with more frequent erythropoietin use requires further study.

Topics: Altitude; Creatinine; Cross-Sectional Studies; Erythropoietin; Female; Humans; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Urea; Uremia

This study examines the role of uraemia and the effect of different dialysis treatments on red cell cation transport. We evaluated the main cation transport systems in erythrocytes of non-dialysed end-stage renal disease (ESRD) subjects, of patients undergoing haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), as well as the changes induced by human recombinant erythropoietin (r-HuEPO) administration. In uraemic undialysed and dialysed patients, we observed an increase in K/Cl co-transport activity and in shrinkage-induced amiloride-sensitive (HMA-sensitive) Na efflux (Na/H exchange) and a decrease in Na/K pump and Na/K/Cl co-transport activity, while Na/Li exchange was increased only in dialysed patients. In uraemic erythrocytes, we showed for the first time an increased K/Cl co-transport activity, which was cell age independent. Generally, the different method of dialysis (CAPD or HD) did not modify the cation transport abnormalities observed. During the treatment with r-HuEPO, all the systems, with the exception of the Na/K pump and Na/K/Cl co-transport, increased their activities following the increase of circulating young red cells. The changes produced under r-HuEPO administration were transient and cation transports returned to the baseline values within 100 days of treatment, indicating a primary and prominent pathogenetic role of uraemia in modulating the red cell membrane cation transport activities.

Topics: Anemia; Chlorides; Erythrocytes; Erythropoietin; Humans; Ion Transport; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Potassium; Renal Dialysis; Renal Replacement Therapy; Sodium; Uremia

The results of the studies reported here demonstrate the cardiac non-haematopoietic effect of erythropoietin, providing a new physiological function of the hormone. We demonstrate that myocardium from rat with chronic renal failure (CRF) showed an abnormal response to ouabain associated with an inhibition of cardiac Na+/K+/ATPase activity and with a decrease in the high affinity 3H-ouabain binding sites. The extent to which both actions were improved with the recombinant human erythropoietin (rHuEpo) treatment suggests that the lack of the hormone is responsible for this phenomenon. The fact is that neither contractile nor enzymatic action of rHuEpo was accompanied with the improvement of the functional renal and haematologic parameters, indicating a primary effect on myocardial contractile function of rHuEpo, independent of the anaemic and uraemic state of the animal. The reason why erythropoietin is able to modulate directly the cardiac Na+/K+ pump makes it possible to conclude that the lack of erythropoietin in CRF may be at least in part responsible for the inhibition of cardiac enzymes, altering the contractile behaviour of the heart.

Topics: 4-Nitrophenylphosphatase; Anemia; Animals; Cardiotonic Agents; Dose-Response Relationship, Drug; Erythropoietin; Heart; Humans; Kidney Failure, Chronic; Male; Ouabain; Rats; Rats, Wistar; Recombinant Proteins; Uremia

1. There is no experimental proof that renal insufficiency is a necessary condition for hypertension during erythropoietin treatment. 2. The present study compares the effect of 3 weeks treatment with r-hu EPO (50 i.u./kg) on systolic blood pressure (SBP), haematocrit and plasma cGMP in an animal model of chronic renal failure (remnant kidney model excision) and sham-operated rats. 3. Sub-total nephrectomy induced a significant fall in haematocrit and a significant increase in plasma creatinine levels. Treatment with r-hu EPO resulted in a significant haematocrit increase in uraemic as well as in non-uraemic rats. Despite this effect, r-hu EPO treatment had no effect on SBP in sham-operated rats. On the contrary, this treatment caused significant SBP elevation in uraemic rats; in these rats, SBP increase did not correlate with haematocrit increase. 4. Plasma cGMP concentrations were significantly higher in uraemic compared to sham-operated rats and were not modified by r-hu EPO treatment. 5. This study provides evidence that renal insufficiency in rats is a prerequisite for the development of hypertension during erythropoietin treatment.

Topics: Animals; Blood Pressure; Creatinine; Cyclic GMP; Disease Models, Animal; Erythropoietin; Hematocrit; Hypertension; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar; Uremia

We studied 37 hemodialysis patients during hemodialysis in order to assess the effects of dialysis on endogenous plasma coagulation inhibitors (antithrombin III, protein C, free and total protein S). The patients were examined prior to erythropoietin (EPO) treatment, upon reaching target hemoglobin (Hb) and after 3 months at steady state Hb levels. The levels of protein C increased significantly during dialysis. However, EPO treatment did not affect the levels of any of the endogenous coagulation inhibitors, either upon reaching target Hb or after 3 months of steady state Hb. The sequence of change during dialysis of protein C, free and total protein S was constant when comparing respective patterns prior to EPO treatment to those at target Hb and steady state Hb respectively. In conclusion, hemodialysis seems to activate synthesis of endogenous coagulation while partial correction of anaemia with EPO does not affect the levels of these inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Anticoagulants; Antithrombin III; Blood Cell Count; Blood Coagulation; Erythropoietin; Female; Hemoglobins; Heparin; Humans; Male; Middle Aged; Protein C; Protein S; Renal Dialysis; Uremia

The rise in plasma uric acid (UA) in chronic renal failure (CRF) is quite limited. This may be due to either increased extrarenal excretion, diminished biosynthesis, and/or enhanced degradation of uric acid. The intestinal flux studies revealed a striking modification of urate transport from no net flux to a net secretory flux in the jejunum and from a basal net absorptive to a net secretory flux in the colon of CRF animals. In addition, CRF animals showed a marked reduction in hepatic, renal, and enteric tissue xanthine oxidase activity and no significant change in tissue uricase activity. The correction of anemia with erythropoietin did not significantly alter the plasma concentration or urinary excretion of urate. Thus, enhanced enteric excretion and depressed production of uric acid (reduced xanthine oxidase activity) may account for the lack of significant hyperuricemia in CRF.

Topics: Animals; Erythropoietin; Intestinal Mucosa; Kidney; Kidney Failure, Chronic; Liver; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Urate Oxidase; Uremia; Uric Acid; Xanthine Oxidase

The effect of 1-year erythropoietin (rHu-EPO) treatment on the bleeding time, platelet aggregation, ATP and thromboxane B2 (TXB2) release, cyclic AMP (cAMP) concentration and platelet surface positive charge were studied in 8 haemodialysed children with chronic uraemia and 8 controls. The pre-dialysis haematocrit (Hct) was 0.21 + 0.01 before and 0.36 + 0.01 following 1 year of rHu-EPO therapy. At the end of this period the pre-dialysis bleeding time became normal (P < 0.05); this was associated with a significant increase in platelet aggregability (P < 0.05), ATP release (P < 0.05) and TXB2 production (P < 0.01), and with a significant decrease in platelet cAMP concentration (P < 0.01). A further increase in platelet aggregation, ATP release and TXB2 production and a decrease in platelet cAMP concentration was observed following bicarbonate haemodialysis (BHD) (P < 0.01). There was a significant positive correlation between platelet aggregation and ATP release (r = 0.78, P < 0.05), as well as platelet aggregation and TXB2 production (r = 0.68, P < 0.05). A significant negative correlation was found between platelet aggregability and cAMP concentration (r = -0.7, P < 0.05). The platelet surface positive charge, which was significantly lower in the patients than in the controls (P < 0.01), did not change during rHu-EPO therapy, nevertheless BHD resulted in a significant increase (P < 0.05), suggesting the surface charge may influence platelet aggregation. In an in vitro and an in vivo study, rHu-EPO and the higher Hct did not increase platelet aggregation directly. Long-term administration of rHu-EPO stimulated complex functional and biochemical changes in the platelets of uraemic patients, which resulted in an improved aggregability.

Topics: Adenosine Triphosphate; Adolescent; Bicarbonates; Bleeding Time; Blood Platelets; Cyclic AMP; Erythropoietin; Female; Fluorometry; Humans; Male; Membrane Potentials; Platelet Aggregation; Platelet Count; Prospective Studies; Radioimmunoassay; Recombinant Proteins; Renal Dialysis; Thromboxane B2; Uremia

The effect of recombinant human erythropoietin (rHuEPO) on synthesis of methylguanidine was studied in 6 uraemic patients on haemodialysis and 5 uraemic patients on continuous ambulatory peritoneal dialysis (CAPD). The two groups of patients were started on a 24-week course of thrice weekly 1500 IU of rHuEPO by the intravenous route. Serum methylguanidine level and methylguanidine/creatinine ratio were comparable in these groups. In the two groups no significant differences were observed in these measurements comparing the pretreatment values with those 4, 8, 12 or 24 weeks after starting rHuEPO administration. During rHuEPO therapy, serum methylguanidine levels and methylguanidine/creatinine ratio showed no considerable difference between the two groups. These findings suggest that administration of rHuEPO does not alter methylguanidine synthesis in uraemic patients on haemodialysis and CAPD.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Infusions, Intravenous; Male; Methylguanidine; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia

Erythropoietin therapy for uraemic anaemia is associated with a high rate of hypertensive and thrombotic complications. The mechanism is unknown, but a change in cellular calcium control may be relevant to changes in blood pressure and thrombosis. Platelets were utilized as a model of vascular smooth muscle cells. The effects of erythropoietin therapy on platelet cellular calcium, assessed by fura-2, were measured in 25 patients receiving renal replacement therapy during a 6-month treatment period. Three patients failed to reach a target haemoglobin and were excluded from the analysis. Blood pressure increased in 11 of the remaining 22 subjects, eight requiring an increase in antihypertensive medication. There were no differences in cellular calcium control between the group in whom blood pressure rose and patients with stable blood pressure. Overall there was a fall of 24% in resting cytosolic calcium (baseline 69.2 +/- 5.1 to 52.5 +/- 3.0 nmol/l, P < 0.05) after 3 months of erythropoietin therapy. There was no change in the thrombin-stimulated peak response in the presence of extracellular calcium during therapy, although thrombin-stimulated intracellular release also fell at 3 months (baseline 769 +/- 61 versus 3 months 559 +/- 49 nmol/l, P < 0.01). This study suggests that intracellular free calcium control within platelets improves in response to erythropoietin therapy. However these changes appear not to be related to the development of hypertension.

Topics: Adult; Aged; Anemia; Blood Platelets; Blood Pressure; Calcium; Cytosol; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Thrombosis; Uremia

This study aimed to assess the effect of anaemia on volume related hormones in dialyzed patients with chronic uraemia. Three groups of subjects were examined. The first one comprised 34 hemodialyzed patients with severe anaemia (haematocrit value < 28%). 17 patients were treated with EPO for 1 year (EPO group) while the other 17 patients did not receive rHuEPO (no-EPO group) but were intensively monitored biochemically and clinically as patients of the EPO group. The second group (HD) consisted of 12 hemodialyzed uraemic patients with a Hct > 30% without rHuEPO treatment, while the third one comprised 15 healthy subjects. In patients of the EPO and no-EPO group plasma renin activity (PRA), plasma concentration of aldosterone (Ald) atrial natriuretic peptide (ANP and vasopressin (AVP) were assessed before (0) and after 3, 6, 9 and 12 months of clinical monitoring, while in patients of the HD group and in normals the above mentioned parameters were estimated only once. EPO treatment improved significantly the Hct value already after three months of therapy. No significant changes in PRA and plasma concentrations of Ald, ANP and AVP in the noEPO group were noticed during 12 months of monitoring. In contrast EPO treatment induced a significant, although transitory decrease of PRA, Ald and AVP, but an increase of plasma ANP. No influence of rHuEPO therapy on blood pressure was noticed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aldosterone; Anemia; Arginine Vasopressin; Blood Pressure; Blood Volume; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Several alterations in growth hormone (GH) secretion have been reported in patients with chronic renal failure. The aim of the present report has been to assess the effect of acutely administered recombinant human erythropoietin (rHuEPO) infusion on GH responses to thyrotropin-releasing hormone (TRH) in uremic patients. Twelve male patients (mean age 46.2 years, range 24 to 69) were studied. Seven of them were on continuous ambulatory peritoneal dialysis (CAPD), two on chronic hemodialysis (HD) and two in pre-dialysis (PreD). None had been treated before with rHuEPO. Each patient was tested with TRH (400 micrograms i.v. in bolus), and with TRH plus rHuEPO (40 U/kg in constant infusion for 30 min) on different days. TRH administration provoked a paradoxical response of GH (peak > 5 micrograms/liter) in nine (5 CAPD, 2 HD, 2 PreD) out of 12 patients. In this group of patients with anomalous GH responses, rHuEPO infusion produced an abolishment of the paradoxical responses (GH peak < 5 micrograms/liter) in eight patients and a marked decrease in a further one. On the contrary, in patients with no paradoxical GH response, stimulation with TRH plus rHuEPO did not induce any change in GH release compared with that observed after TRH alone. rHuEPO had no effect on TRH-induced thyrotropin release. These results suggest that the paradoxical GH response to TRH in patients with chronic renal failure is blocked by rHuEPO administration. This rHuEPO action might be mediated by an increased release of somatostatin or an inhibited GH-releasing hormone secretion.

Topics: Adult; Aged; Drug Combinations; Erythropoietin; Growth Hormone; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Pituitary Gland; Recombinant Proteins; Renal Dialysis; Thyrotropin-Releasing Hormone; Uremia

Children with end stage renal failure and anaemia have an increased cardiac index and often gross ventricular hypertrophy. Correction of anaemia with recombinant human erythropoietin (r-HuEpo) for less than six months results in a reduction in the cardiac index without a significant reduction in left ventricular hypertrophy. Seven children receiving dialysis (group 1) were studied to determine whether a reduction in left ventricular hypertrophy would occur after a 12 month period of r-HuEpo. A decrease in the cardiac index was seen by six months, and a significant reduction in left ventricular mass index and cardiothoracic ratio was seen by 12 months. Successful renal transplantation also results in a reduction in the cardiac index and left ventricular hypertrophy, but the relative contributions of correction of anaemia and correction of biochemical disturbance is unknown because they usually improve simultaneously. To investigate this, six children (group 2) who already had a mean haemoglobin concentration of 107 g/l while receiving dialysis were followed up for 12 months after successful transplantation. They showed no significant change in haemoglobin concentration, but a dramatic improvement in biochemistry. There was no significant change in cardiovascular function. Anaemia is the more dominant influence on cardiovascular function in end stage renal failure.

Topics: Adolescent; Anemia; Child; Child, Preschool; Erythropoietin; Female; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Kidney Transplantation; Male; Recombinant Proteins; Renal Dialysis; Uremia

Subcutaneous injections of recombinant human erythropoietin (rHuEPO) produce considerable pain which can result in noncompliance. As a prelude to an investigation of the possible use of local anesthetics as additives to subcutaneous rHuEPO, we examined the effect of the addition of lidocaine on the erythropoietic properties of rHuEPO. Two weeks after 5/6 nephrectomy, 22 rats were randomly assigned to the following groups: normal saline, rHuEPO, lidocaine, and rHuEPO plus lidocaine. Injections were given three times a week for 2 weeks. No change in hematocrit was observed in the saline and lidocaine groups. The hematocrit of the rHuEPO rats increased from 44.5 +/- 1.4% (mean +/- SD) to 61.6 +/- 2.1% (P < 0.0005), and that of the rHuEPO plus lidocaine group from 42.8 +/- 4.3% to 63.9 +/- 3.0% (P < 0.005), with no difference between the groups. We conclude that the combination of rHuEPO plus lidocaine is as effective as rHuEPO alone in increasing the hematocrit of rats with chronic renal failure.

Topics: Animals; Creatinine; Drug Combinations; Erythropoiesis; Erythropoietin; Lidocaine; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Uremia

The purpose of this study was to investigate the metabolism of erythropoietin (EPO) in uremia compared with healthy subjects. Twenty-one patients (nine men and 12 women) with end-stage renal failure and anemia and 12 healthy volunteers (3 women and nine men) were studied. The pharmacokinetic parameters were calculated after an i.v. and a femoral sc injection of 100 U/kg of recombinant human EPO. The serum EPO (s-EPO) was measured by radio-immunoassay at regular intervals until 48 h (i.v.) and 120 h (sc). In uremia, the median terminal elimination half-life was significantly longer (8.31 versus 4.92 h; P < 0.001) and the clearance was reduced (5.00 versus 7.88 mL/min per 1.73 m2; P < 0.01). The volume of distribution was (3.70 versus 3.31 L/1.73 m2) not significant. The estimated endogenous EPO production was significantly lower in uremia (146 versus 290 U/day per 1.73 m2; P < 0.001). After sc administration, the bioavailability was significantly lower in the patients (23.7 versus 38.5%; P < 0.01), and the maximal s-EPO was lower (113 versus 153 U/L; P < 0.05) and delayed (15.4 versus 11.0 h; P < 0.02), but the mean input time (sc) was not significantly different (23.3 versus 27.8 h). The basal s-EPO was lower in the uremic patients (20.0 versus 26.3 U/L; P < 0.05). There was no difference between patients treated with hemodialysis and peritoneal dialysis or between uremic men and women. There was no correlation between the pharmacokinetic parameters and age.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Absorption; Adult; Aged; Biological Availability; Case-Control Studies; Erythropoietin; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Erythropoietin; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Uremia

1. The effect of erythropoietin and some trace elements on superoxide dismutase (SOD) activity of dialysis patients have been studied. 2. SOD activity of dialysis patients was found to be decreased. 3. The effect of erythropoietin on SOD activity was not found in vitro. 4. Plasma and erythrocyte aluminum increased in dialysis patients, but no significant change in plasma copper was found. 5. Plasma zinc levels of dialysis patients were found to be decreased. 6. These results suggest that inhibition of erythrocyte SOD activity of dialysis patients may contribute to their anemia.

Topics: Adult; Aluminum; Anemia; Copper; Dose-Response Relationship, Drug; Erythrocytes; Erythropoietin; Female; Humans; Male; Metals; Renal Dialysis; Superoxide Dismutase; Uremia; Zinc

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Recombinant Proteins; Uremia

The influence of body iron stores on the concentration of serum erythropoietin was studied in 48 hemodialyzed patients not receiving human recombinant erythropoietin, androgens or iron supplements. The serum erythropoietin concentration was 11.6 +/- 10.4 mIU/ml. There was no correlation between the serum erythropoietin and the hematocrit or hemoglobin concentration; however, there was a correlation between the serum erythropoietin and the log of serum ferritin (r = -0.5699, p < 0.01). Serum erythropoietin levels were higher in the 18 ferropenic patients (serum ferritin < 50 ng/ml) than in the 30 patients with normal serum ferritin concentration (18 +/- 13.8 vs. 7.8 +/- 4.7 mIU/ml, p < 0.01). The administration of intravenous iron to the ferropenic patients resulted in a reduction in serum erythropoietin independent of the response of the anemia (18 +/- 13.8 basal and 7.9 +/- 6.5 mIU/ml at 4 weeks, p < 0.01). Our data would suggest that the concentration of erythropoietin in hemodialyzed patients is influenced by the serum ferritin level.

Topics: Adult; Aged; Anemia, Hypochromic; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Uremia

Topics: Combined Modality Therapy; Erythropoietin; Humans; Recombinant Proteins; Renal Dialysis; Uremia; von Willebrand Factor

Many in vitro studies demonstrate various stimulatory effects of red blood cells (RBC) on T cell reactivity. Only a few suggest a role for RBC in vivo, such as decreased B and T cell function in iron deficiency anemia. Immune deficiency of uremia is only partially corrected by dialysis treatment. We postulated therefore that this anemia may contribute in part to the immune deficiency of uremia. The aim of our study was to evaluate this postulate and to investigate the role RBC may have in the immune system in vivo. The in vitro secretion of interleukin-2 (IL-2), gamma-interferon (gamma-IFN), tumor necrosis factor (TNF) and colony stimulating factor (CSF) by human peripheral blood mononuclear cells isolated from patients and controls was used as a measure of immune function. The following protocols were carried out: IL-2 secretion was measured in patients with end-stage renal disease (ESRD) and in controls. RBCs were transfused to patients with ESRD and secretion of cytokines was measured before, and 4 hours, 4, 7 and 14 days afterwards; patients with ESRD received recombinant human erythropoietin (rHuEpo) and secretion of cytokines was measured before treatment and two and four months later. Finally, the effect of phlebotomy and transfusion of the autologous blood on cytokine secretion in healthy subjects was measured. Secretion of IL-2 by patients with ESRD was substantially lower than that of healthy subjects. In each group, IL-2 secretion correlated positively with hemoglobin level, r = 0.73, P < 0.01 and r = 0.71, P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Bloodletting; Cytokines; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Interleukin-2; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Reference Values; Uremia

Since recombinant human erythropoietin (r-Hu EPO) has been introduced to the treatment of anemia in uremic patients the issue of optimal therapy appeared. For proper erythropoiesis not only erythropoietin but also iron, folic acid and B12 vitamin are needed. Iron deficiency is one of the most common factors causing resistance to r-Hu EPO in uremic patients, so its recognition and eventual supplementation is required for optimal hemopoietic response. The aim of presented study, besides monitoring hematological changes, was to measure iron status parameters such as iron, transferrin, ferritin and percentage of hypochromic erythrocytes and estimation of their usefulness in monitoring iron deficiency during r-Hu EPO treatment.

Topics: Adult; Aged; Anemia; Erythrocyte Count; Erythropoietin; Ferritins; Hemoglobins; Humans; Iron; Middle Aged; Monitoring, Physiologic; Recombinant Proteins; Transferrin; Uremia

Recombinant human erythropoietin (r-Hu EPO) therapy improves the anaemia of patients on chronic hemodialysis, on peritoneal dialysis and those with chronic renal failure who have not yet started any form of renal replacement therapy. In the last category there is concern that r-Hu EPO therapy may be associated with deterioration of the reserve renal function. But new data showed that even during more prolonged treatment the correction of anaemia does not have a major detrimental effect on renal function. The study was undertaken to examine the influence of r-Hu EPO therapy on renal function and rheological erythrocytes finding in uremic rats.

Topics: Animals; Creatinine; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Male; Rats; Rats, Wistar; Recombinant Proteins; Urea; Uremia

Exacerbation of secondary hyperparathyroidism (as manifested by calcium deposits and local inflammation in periarticular tissues) has been reported in haemodialyzed (HD) uraemic patients treated with recombinant human erythropoietin. However, short-term treatment with recombinant human erythropoietin (r-Hu EPO) did not influence significantly plasma levels of parathyroid hormone (PTH), calcitonin (CT) and 25-hydroxycholecalciferol (25-OHD3) in uraemic HD patients. The present study aimed to assess the effect of long-term r-Hu EPO therapy for 12 months on plasma PTH, CT, 25-OHD3 and 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) in uraemic HD patients.

Topics: Adult; Alkaline Phosphatase; Calcium; Erythropoietin; Female; Hormones; Humans; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Reference Values; Renal Dialysis; Uremia

The pathogenesis of hypertension induced by recombinant human erythropoietin (rHuEPO) remains a subject of intense interest. The observation that patients treated with antiplatelet drugs never developed hypertension following rHuEPO therapy prompted us to study retrospectively the incidence and risk factors associated with the development of hypertension in 91 patients on renal replacement therapy who had commenced rHuEPO therapy in the last three years. Logistic regression analysis was used to determine the risk factors associated with the development or aggravation of hypertension during the first six months on rHuEPO therapy. The predictors were: age, gender, number of months on dialysis, antecedent of hypertension, use of antiplatelet drugs, and those parameters related with dose, route and magnitude of the hematological response to rHuEPO. Of the 91 patients studied, 34 developed hypertension (37%). Of the 34 patients who were on antiplatelet treatment, 2 (5.8%) developed hypertension, whereas among 57 who did not receive antiplatelet drugs, 32 (56%) developed it. By multiple logistic regression analysis, the best predictive variables over the development of hypertension were: age (odds ratio: 0.959, P = 0.02), antecedent of hypertension (odds ratio: 6.52, P = 0.002), and use of antiplatelet therapy (odds ratio: 0.030, P < 0.0001). The rest of the studied variables failed to explain the development of hypertension. Antiplatelet therapy may prevent the development of hypertension in patients treated with rHuEPO. Since the antiplatelet drugs used in this study did not have a significant hemodynamic effect, we infer that changes in platelet aggregability induced by rHuEPO may be involved in the pathogenesis of hypertension induced by this hormone.

Topics: Adolescent; Adult; Aged; Catheters, Indwelling; Confounding Factors, Epidemiologic; Erythropoietin; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Platelet Aggregation Inhibitors; Recombinant Proteins; Regression Analysis; Renal Dialysis; Retrospective Studies; Risk Factors; Thrombosis; Uremia

We have retrospectively analysed sera from 52 already sensitized uraemic patients collected over 1 year and compared erythropoietin (EPO)-treated with non-EPO-treated patients. Significantly fewer (P<0.01) patients (33%) on dialysis because of the rejection of their kidney grafts received EPO than patients on dialysis because of underlying kidney disease (71%). EPO treatment reduced the number of additional blood transfusions, since 3/28 EPO-treated but 12/24 non-EPO-treated patients were given blood (P<0.05). Among the EPO-treated patients, 64% showed a loss of panel-reactive antibodies (PRA), as measured by the micro-lymphocytotoxic technique, while only 12.5% of the non-treated patients showed a loss of PRA (P<0.01). In the subgroup of transplanted patients, PRA loss was only found among the EPO-treated patients, but their number was small (P<0.05). The class, subclass and specificities of the antibodies, as determined by FACS (flow cytometry) analyses, showed no distinct differences between EPO- and non-EPO-treated patients. The differences were significant between transfused and previously transplanted patients.

Topics: Anemia; Antibodies; Erythropoietin; Humans; Immunoglobulin A; Immunoglobulin M; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Retrospective Studies; T-Lymphocytes, Cytotoxic; Uremia

Thrombotic events sometimes complicate erythropoietin therapy. Fibrinolytic system may play a role in their pathogenesis. The studies were performed on 22 chronically hemodialyzed patients with end-stage renal failure treated with recombinant human erythropoietin (rHuEPO, Eprex, Cilag) for 12 weeks. Alpha 2 antiplasmin (alpha 2AP), antithrombin III (AT III), C1 esterase inhibitor (C1 INH), plasminogen activator inhibitor (PAI) activities, alpha 2macroglobulin (alpha 2M), fibrinogen, fibrin monomers concentration and euglobulin clot lysis time (ECLT) were measured before and after 1, 2, 4, 8 and 12 weeks of rHEPO therapy. A fall in PAI activity (p < 0.05) was found after 1 week, while alpha 2AP and C1 INH activities decreased after 12 weeks of the therapy (p < 0.001 and p < 0.05, respectively). The activity of AT III, the main inhibitor of the coagulation cascade fell after 4 weeks of the treatment with rHuEPO (p < 0.001). Fibrin monomers concentration was found to be decreased after 12 weeks of rHuEPO administration. Fibrinogen and alpha 2M concentration showed no statistically significant changes during rHuEPO therapy. A decrease in plasma fibrinolytic inhibitor activities may be considered as a protective mechanism against thrombotic tendency observed during rHuEPO therapy.

Topics: Adult; Erythropoietin; Female; Fibrinolysis; Humans; Male; Recombinant Proteins; Uremia

Topics: Animals; Erythropoietin; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Uremia

Topics: Adolescent; Adult; Erythrocytes; Erythropoietin; Female; Humans; Male; Middle Aged; Osmolar Concentration; Recombinant Proteins; Renal Dialysis; Uremia; Vitamin E

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Hepatitis C; Hepatitis, Chronic; Humans; Middle Aged; Nephrectomy; Renal Dialysis; Uremia

The normal response to 45 degrees head-up tilt (decreased stroke volume and cardiac output and increased heart rate and peripheral resistance) is not seen in the majority of haemodialysis patients. This is due to both an abnormal baroreceptor reflex and increased venous tone which may be explained by a number of factors including hypoxia, acidosis and sodium retention. We have studied this response by impedance cardiography in eight chronic haemodialysis patients, both before and after 3 months of treatment with human recombinant erythropoietin. Before treatment the cardiovascular parameters were abnormal both at rest and on tilting in each patient. The change in each measurement following tilting was: stroke volume, 0.5 +/- 6%; cardiac output, 6 +/- 5%; peripheral resistance, -8 +/- 4%; and heart rate, 10 +/- 4%. After 3 months of erythropoietin (150 U/kg/week intravenously) the mean haematocrit had risen from 19.5 +/- 3% to 32.9 +/- 4% and all patients felt physically fitter. Impedance showed no change in the supine-indices but after tilting there was a dramatic fall in stroke volume (-26 +/- 7%) and cardiac output (-17 +/- 7%) and an increase in heart rate (15 +/- 4%) and peripheral resistance (28 +/- 10%) each moving towards the normal response. These results indicate that human recombinant erythropoietin normalizes the response to postural stress in these patients and suggest that anaemia is the principal cause of the abnormal venoconstriction seen in haemodialysis patients. The mechanisms involved warrant further investigation.

Topics: Adult; Baroreflex; Erythropoietin; Female; Hemodynamics; Humans; Male; Middle Aged; Posture; Recombinant Proteins; Renal Dialysis; Stress, Physiological; Uremia

Topics: Aged; Drug Interactions; Erythropoietin; Hematocrit; Hepatitis C; Humans; Interferon-alpha; Kidney Neoplasms; Male; Renal Dialysis; Uremia

An important role in the formation of haemostasis defects in haemodialysed patients play phospholipids. The disturbances of platelet activity play an essential part in platelet structure and function. In uraemic patients changed plasma lipid pattern is observed, as well as positive influence of human recombinant erythropoietin (rhuEPO) on some plasma lipid disorders in these patients. The aim of this study was to investigate rhuEPO influence on platelet phospholipid composition in haemodialysed patients. RhuEPO was applied subcutaneously, 2000j twice a week. Before rhuEPO treatment significant decrease of phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylcholine (PC) contents was observed, as compared with control group. After rhuEPO treatment a significant increase of PE and PC contents was noted. The obtained results suggest that rhuEPO partially normalizes changed platelet phospholipids composition, but detailed mechanism of this influence is unclear.

Topics: Adult; Blood Platelets; Drug Administration Schedule; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Phosphatidylethanolamines; Phosphatidylinositols; Recombinant Proteins; Renal Dialysis; Uremia

The correction of renal anemia by recombinant human erythropoietin (rHuEPO) makes it possible to assess the effect of anemia on uremic cardiopathy (UC). So far, conflicting results have been reported. We studied 10 hemodialyzed patients aged (51 +/- 18 years, dialytic age 47 +/- 18 months) before and after rHuEPO treatment. All patients underwent an echocardiogram before, and six months after stable hematocrit (31 +/- 2) was obtained. The results show a reduction in LVDD. No improvement in ejection fraction and in ventricular hypertrophy was observed, probably owing to an increase in blood pressure. Finally, there is a possibility that the myocardium of hemodialyzed patients undergoes anatomical changes which may not improve, even after anemia correction.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Heart Diseases; Humans; Male; Middle Aged; Recombinant Proteins; Uremia; Ventricular Function

28 anemic [hematocrit (Hct) < 25%] and normotensive patients on maintenance hemodialysis with uremia-associated left-ventricular (LV) hypertrophy were treated with recombinant human erythropoietin. Before correction of anemia, after 4 months at a target Hct of 35% and 16 months (Hct still 35%) patients were assessed by echocardiography and physical stress testing. Partial correction of anemia resulted in a decrease in the LV end-diastolic diameter from 52.6 +/- 3.4 SD mm to 49.6 +/- 3.4 mm at 4 months (p < 0.01) and 47.9 +/- 2.9 mm at 16 months (p < 0.001). Concomitantly there was a slight decrease of LV end-systolic diameter (30.4 +/- 3.1 vs. 32.6 +/- 3.5 mm, p < 0.05) and LV posterior wall thickness (12.1 +/- 0.9 vs. 12.8 +/- 0.8 mm, p < 0.05) at 16 months. The calculated LV muscle mass index was reduced from 199 +/- 35 g/m2 to 173 +/- 34 g/m2 at 4 months (p < 0.01) and 160 +/- 28 g/m2 at 16 months (p < 0.001). Heart rate at rest was reduced significantly from 80 +/- 12 to 73 +/- 11 min (p < 0.01) at 4 and 16 months. LV ejection fraction, thickness of LV septum and blood pressure did not change. Partial correction of anemia led to an increase of maximal physical stress tolerance from 1.4 +/- 0.4 to 1.85 +/- 0.5 W/kg b.w. at 4 months (p < 0.01), which was maintained at 16 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Pressure; Erythropoietin; Female; Heart Rate; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Dialysis; Time Factors; Uremia; Ventricular Function, Left

This paper describes how Bayesian networks can be used in combination with compartmental models to plan recombinant human erythropoietin delivery in the treatment of anemia of chronic uremic patients. Past measurements of hemoglobin concentration in a patient during the therapy can be exploited to adjust the parameters of a compartmental model of erythropoiesis. This adaptive process provides more accurate patient-specific predictions, and hence a more rational dosage planning. Inferences are performed by using a stochastic simulation algorithm called Gibbs sampling. We describe a drug delivery optimization protocol based on our approach. Some results obtained on real data are presented.

Topics: Adult; Anemia; Bayes Theorem; Chronic Disease; Computer Simulation; Costs and Cost Analysis; Drug Administration Schedule; Drug Therapy, Computer-Assisted; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Male; Models, Biological; Uremia

Five patients with erythrocytosis associated with renal failure on maintenance hemodialysis were investigated for in vitro erythroid progenitor growth and the effect of their uremic sera on normal erythropoiesis. The duration of hemodialysis prior to discovery of erythrocytosis ranged from 1 week to 96 months. None had acquired cystic disease and no other known cause of increased erythropoietin (Epo) production was identified. With the presence of Epo in cultures, all five patients grew erythroid colonies within normal or higher than normal ranges. Three patients formed spontaneous erythroid colonies in the absence of added Epo; all three fulfilled the clinical diagnosis of polycythemia vera (PV). The uremic sera from patients with PV lacked either a stimulating or an inhibiting effect on normal erythropoiesis. The association between renal failure and PV was coincidental. The other two patients without endogenous erythroid colony formation had enhanced erythropoietic activity in their sera, which increasingly stimulated the erythroid colony growth by normal bone marrow cells as the concentration of the uremic serum was increased. The etiology of increased Epo production in these 2 patients remained undefined during long-term follow-up. The present study on five uremic patients with polycythemia showed two different underlying mechanisms of erythrocytosis--characteristic autonomous erythroid proliferation for PV in three patients and inappropriate idiopathic Epo production in two patients.

Topics: Aged; Blood Cells; Bone Marrow Cells; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Kidney; Liver; Male; Middle Aged; Polycythemia; Renal Dialysis; Renal Insufficiency; Ultrasonography; Uremia

We studied the effects of self-administered, daily, low-dose, subcutaneous (SC) erythropoietin (EPO) therapy in 15 uremic patients on continuous ambulatory peritoneal dialysis (CAPD) for 16 weeks to assess its efficacy and safety. The patients had baseline hemoglobin (Hb) levels of < 8 g/dl and were started on 10 u/kg/day of beta-EPO. The dosage of EPO was adjusted every 4 weeks according to hematological response. The patients learned to inject into their thighs themselves. Hb increased significantly from 6.6 +/- 0.2 g/dl (mean +/- SEM) at week 0 to 9.0 +/- 0.3 at week 8 and 10.0 +/- 0.4 at week 16 (p < 0.0001). Hematocrit (Hct) increased significantly from 0.20 +/- 0.01 at week 0 to 0.27 +/- 0.01 at week 8 and 0.29 +/- 0.001 at week 16 (p < 0.0001). The mean EPO dose was 10 u/kg/day at week 0 and 10.5 +/- 0.4 at week 8 and 10.3 +/- 0.5 at week 16. After minor adjustments in antihypertensive therapy had been made no significant differences in mean arterial blood pressure were noted. Six of 15 patients required increased dosage of antihypertensive drugs. All patients were given oral iron supplements. There was a significant decrease in percentage of transferrin saturation and 10 patients required additional intravenous iron supplements. There was no significant difference in the serum levels of creatinine, albumin, potassium, phosphate and urate with EPO treatment. There were no local complications at the sites of injection and the injections themselves were quite painless.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Self Administration; Uremia

The increased risk of hypertension during treatment of uraemic patients with recombinant human erythropoietin (rHuEpo) has been related to increased blood viscosity. We therefore studied rheological parameters determining whole blood viscosity in seven haemodialysed uraemic children and adolescents during treatment with rHuEpo (initial dose 75 IU/kg per week). Before treatment the patients were anaemic and had reduced red blood cell (RBC) deformability at low shear stress of 0.7 Pa in the rheoscope compared with six healthy control children (0.14 +/- 0.03 versus 0.19 +/- 0.02). The RBC membrane rigidity (i.e. membrane elastic shear modulus) determined in a flow channel was increased (2.04 +/- 0.26 versus 1.36 +/- 0.05 x 10(-5) N/m). After two weeks of rHuEpo, RBC deformability improved and RBC membrane rigidity decreased significantly. With increasing doses of rHuEpo the haematocrit rose steadily. After 14 weeks of therapy RBC deformability reached control values, and after 30 weeks RBC membrane rigidity became normal. RBC aggregation and plasma viscosity were similar in patients and controls and did not change significantly in response to rHuEpo. The early improvement of RBC deformability may lead to an increase in tissue oxygenation by facilitating microcirculatory blood flow.

Topics: Adolescent; Anemia; Blood Viscosity; Child; Erythrocyte Aggregation; Erythrocyte Deformability; Erythropoietin; Female; Humans; Male; Rheology; Uremia

Using 31P-nuclear magnetic resonance (NMR) measurements of relaxation rate for 2,3 diphosphoglycerate (DPG) phosphorus atoms, we showed previously that in uraemic red blood cells the DPG-haemoglobin binding is stronger, thus stabilizing the deoxyhaemoglobin form and hence facilitating oxygen release. Here we verified if these modifications of spatial environment of DPG remain in uraemic patients treated by human recombinant erythropoietin (rHuEpo). Simultaneously we measured the intraerythrocytic ATP concentration (ATPi) and pH (pHi) of patients. Our results show a slight decrease on pHi and ATPi values during rHuEpo treatment. For the DPG relaxation rates, we observed a very weak but statistically significant increase 6 months after the beginning of treatment, but we cannot attribute a physiopathological significance to these results because of the lack of accuracy of the NMR determination of relaxation rate in red blood cells. Therefore, the DPG-haemoglobin binding is always stronger than in normal subjects.

Topics: 2,3-Diphosphoglycerate; Adenosine Triphosphate; Adult; Aged; Anemia; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Protein Binding; Recombinant Proteins; Uremia

Topics: Aluminum; Anemia; Bone Diseases, Metabolic; Drug Resistance; Erythropoietin; Humans; Iron; Uremia

Topics: Erythropoietin; Histamine; Humans; Pruritus; Renal Dialysis; Uremia

The use of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of renal anemia, but the dose regimens, the optimal frequency, and the effects on other target organs like the central nervous systems (CNS) are still under discussion. We designed a prospective, ongoing study with 10 stable continuous ambulatory peritoneal dialysis (CAPD) patients (6 males, 4 females; mean age 64.4 +/- 7.8 years), with a pretreatment hemoglobin (Hb) < 7.0 g% and requiring regular blood transfusions. Seven patients were treated with 4000 U rHuEPO once weekly (Eritrogen, Boehringer Mannheim), 2 patients received 4000 U every 5 and 8 days, and the last one 4000 U every 10 days. The target hematocrit was 33% and Hb 10.0 g%. The CNS activity was recorded as visual (VEP), brainstem (BAER), and somatosensory (SEP)-evoked potentials. The mean Hb concentration increased from 6.9 +/- 1.2 g% to 10.3 +/- 1.6 g% (p < 0.001) over 8 weeks. There were no significant changes in urea, creatinine, and potassium levels, and urine output. rHuEPO induced a decrease in latency of P100 VEP, in the four main components of BAER, and in the P27-N35 intertime of SEP. Parallel to the improvement of red cell indices, patients experienced a dramatic improvement in well-being. The subcutaneous administration of a single vial of rHuEPO is safe, convenient, and inexpensive in CAPD. The role of rHuEPO treatment in improving the electrophysiological brain function in uremic and anemic patients remains to be studied and may not necessarily be based on improved cerebral oxygenation.

Topics: Aged; Anemia; Erythropoietin; Evoked Potentials; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Prospective Studies; Recombinant Proteins; Uremia

The purpose of this work was to study the effects of correcting anemia on the distribution and partition of body fluids in dialyzed uremic subjects. We studied nine (7 m, 2 f) patients before and three months after the start of i.v. treatment with rHu-EPO, measuring total body water (TBW) with 3H2O, extracellular fluid volume (ECFV) with 35SO4 and plasma volume (PV) with 125I-SA. The intracellular water (ICW) and the interstitial fluid volumes (IFV) were derived by calculation from those measurements. The total blood volume (TBV) was calculated from the PV and the packed cell volume (PCV). Mean TBW, 482 +/- 45 (M +/- SD) ml/kg/bw and ECFV, 168 +/- 27.5 ml were significantly lower in patients than in nine matched normal controls, while the mean ICW (315 +/- 43 ml/kg) was similar. PCV before the start of rHu-EPO was 17.2 +/- 2.9% and had risen significantly to 31.3 +/- 4.8% (p = 0.000) after three months of therapy. Body weight (58 +/- 13 kg), TBW, ECFV and ICW did not change. TBV before rHU-EPO was 68.7 +/- 7.5 ml/kg and remained nearly unchanged, while PV fell significantly from 57 +/- 9 to 48 +/- 8 ml/kg (p < 0.025), with the calculated IFV rising from 111 +/- 25 to 127 +/- 27 (p = 0.000). The PV/IFV ratio decreased from 0.53 +/- 0.12 to 0.38 +/- 0.09 (p = 0.001). The decrease in PV/IFV ratio was paralleled by simultaneous increase in PCV in all but one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Volume; Erythrocyte Volume; Erythropoietin; Extracellular Space; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Anemia is common in patients with chronic renal insufficiency and secondary hyperparathyroidism. Erythropoietin therapy is effective, but the dose required varies greatly. One possible determinant of the efficacy of erythropoietin therapy is the extent of marrow fibrosis caused by hyperparathyroidism. We examined the relation between the erythropoietic response to erythropoietin and hyperparathyroidism in a cross-sectional study of 18 patients undergoing hemodialysis who had received erythropoietin therapy for one to three years. In 7 patients (the poor-response group), the dose of intravenous erythropoietin needed to maintain a mean (+/- SD) target hematocrit of 35 +/- 3 percent was > 100 units per kilogram of body weight three times a week, and in 11 patients (the good-response group) it was < or = 100 units per kilogram. In all patients, indexes of the adequacy of dialysis and the extent of hyperparathyroidism and aluminum toxicity were determined monthly, and bone histomorphometry was performed.. The mean (+/- SD) dose of erythropoietin required to maintain the target hematocrit was 174 +/- 33 units per kilogram three times a week in the poor-response group and 56 +/- 18 units per kilogram in the good-response group. The mean ages, duration and adequacy of dialysis, increment in hematocrit, iron requirements, and serum concentrations of calcium, phosphate, and aluminum were similar in the two groups. The percentages of osteoid volume and surface, the osteoid thickness, and the stainable aluminum content of bone were similar in the two groups. In contrast, the mean serum parathyroid hormone concentration, the percentages of osteoclastic and eroded bone surfaces, and the degree of marrow fibrosis were greater in the poor-response group than in the good-response group (P = 0.03, P = 0.04, P = 0.009, and P = 0.009, respectively).. In patients with uremia, the dose of erythropoietin needed to achieve an adequate hematocrit response may depend on the severity of secondary hyperparathyroidism and the extent of bone marrow fibrosis.

Topics: Adult; Aged; Anemia; Cross-Sectional Studies; Erythropoietin; Female; Hematocrit; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Primary Myelofibrosis; Prospective Studies; Renal Dialysis; Uremia

Serum levels of monokines, including macrophage colony-stimulating factor (M-CSF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and IL-1 beta (IL-1 beta), were measured in patients with chronic renal failure in an attempt to clarify the kinetics of these cytokines in the course of renal anemia. M-CSF was the only monokine detectable in the serum from all patients as well as healthy donors, making this cytokine feasible and reliable for serial evaluations. On all occasions, the level of M-CSF in uremic patients was significantly higher than that in healthy donors (29.4 +/- 12.3 vs. 5.5 +/- 1.1 ng/mL). In patients undergoing hemodialysis, the serum level of M-CSF was greater than that in patients undergoing continuous ambulatory peritoneal dialysis or in uremic patients without dialysis therapy. No difference was observed, however, in the levels of IL-1 alpha, IL-1 beta and TNF-alpha levels in these groups. Patients with severe anemia were subsequently treated with 60 to 80 U/kg per week of human recombinant erythropoietin (rhEpo) for 3 months. After this replacement therapy, hemoglobin levels increased with a variable change ranging from 0 to 3.5 g/dL. The pretherapy M-CSF level, however, was found to predict statistically the response to the therapy (p < 0.05). Patients with a lower pretherapy value responded better to rhEpo therapy; those with a higher level showed a minor degree of response. From these results, we postulate that the elevated M-CSF serum level in uremic patients is in part a consequence of the dialysis procedure and that rhEpo therapy is more effective in patients who are under sophisticated dialysis protocol and have a lower M-CSF level.

Topics: Erythropoietin; Hemoglobins; Humans; Interleukin-1; Macrophage Colony-Stimulating Factor; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Tumor Necrosis Factor-alpha; Uremia

Even though there is extensive evidence that uremia affects the fragility and deformability of red blood cells (RBCs), essentially all data on the RBC membrane permeability have been obtained with nonuremic blood. Permeability data were obtained for creatinine and uric acid, two metabolites of interest in hemodialysis, using a stirred ultrafiltration device with direct cell- and protein-free sampling. Experiments examined the effects of temperature and suspending phase on solute transport for both normal and uremic blood cells. Creatinine and uric acid transport from normal RBCs at 37 degrees C were characterized by saturation half-times of 40 +/- 10 minutes and 54 +/- 12 minutes, respectively. The corresponding half-times for uremic cells were significantly longer, 94 +/- 26 minutes and 180 +/- 38 minutes. Data indicated that the slower rate of creatinine transport in uremic blood was caused by an alteration in the RBC membrane, while the reduction in uric acid transport was associated with alterations in the uremic plasma. The temperature dependence of the RBC permeability was also much less pronounced for uremic cells for both solutes. These results provide important insights into the effects of uremia on the RBC membrane permeability, and have important implications for dialysis.

Topics: Adult; Aged; Biological Transport; Cell Membrane Permeability; Creatinine; Erythrocyte Membrane; Erythropoietin; Female; Humans; In Vitro Techniques; Kinetics; Male; Middle Aged; Reference Values; Renal Dialysis; Temperature; Uremia; Uric Acid

Recombinant human erythropoietin was administered to 12 patients with end-stage renal failure on long-term hemodialysis. They responded to the therapy with a shortening of the prolonged bleeding time, starting from the 1st week of therapy, before a significant increase in hemoglobin concentration was achieved. We also observed an increase in the activity of tissue plasminogen activator and a decrease in the activity of its inhibitor. There were no changes in platelet count but a significant increase in blood and platelet serotonin concentration was found. The shortening of the prolonged bleeding time before the correction of the anemia correlated with the rise in blood and platelet serotonin concentration during erythropoietin therapy. We suggest the possible involvement of an serotonergic mechanism in the hemostatic action of recombinant human erythropoietin.

Topics: Adult; Anemia; Bleeding Time; Blood Platelets; Erythropoietin; Female; Fibrinolysis; Hemostasis; Humans; Male; Middle Aged; Serotonin; Uremia

Topics: Adult; Bromocriptine; Chronic Disease; Drug Evaluation; Erythropoietin; Humans; Hypogonadism; Kidney Failure, Chronic; Male; Middle Aged; Penile Erection; Recombinant Proteins; Renal Dialysis; Spermatogenesis; Sulfates; Uremia; Zinc; Zinc Sulfate

Absolute or functional iron deficiency decreases the effectiveness of erythropoietin in patients undergoing hemodialysis. We describe a patient who developed pica associated to a ferritin level of 800 ng/ml during recombinant human erythropoietin treatment. The symptom subsided after supplementation with iron dextran. Therefore we recommend iron supplementation during the initial phase of treatment with erythropoietin until serum ferritin levels raise above 1000 ng/ml.

Topics: Adult; Anemia, Hypochromic; Erythropoietin; Ferritins; Glomerulonephritis, IGA; Humans; Immunologic Factors; Iron; Iron Deficiencies; Male; Pica; Protoporphyrins; Recombinant Proteins; Renal Dialysis; Transferrin; Uremia

The effect of recombinant human erythropoietin (rHuEPO) on primary hemostasis was tested in 19 hemodialyzed patients. Bleeding time, platelet aggregation and platelet interaction with vessel subendothelium (SE) under flow conditions were determined before treatment and after patients reached hematocrits greater than or equal to 30%. Two thrombotic events (an acute myocardial infarction and an AV fistula clotting) were recorded during the early stages of treatment. A shortening of average bleeding times (P less than 0.01), an increase in platelet count (P less than 0.01) and an improvement of platelet aggregation (P less than 0.01) and of platelet-SE interaction (P less than 0.01) were observed. A low correlation index was found between hematocrit and bleeding time (r = -0.351, P less than 0.05). To assess a possible effect of rHuEPO on platelet function, the same parameters were evaluated before and after receiving three doses of rHuEPO (40 U/kg i.v. post-hemodialysis) in 14 of the patients. No changes in platelet or erythrocyte counts were observed, the mean bleeding time remained unchanged, but platelet aggregation induced by arachidonic acid (P less than 0.05), ADP (P less than 0.01) and ristocetin (P less than 0.05) improved. Perfusion studies confirmed moderate but significant increases in the parameters that quantify platelet-SE interaction (P less than 0.05). Improvement of ADP-induced aggregation correlated with the increase of platelet adhesion to SE (r = 0.675, P less than 0.05). We conclude that rHuEPO treatment improves primary hemostasis in uremia through an increase of red cell mass but also through a beneficial effect on platelet function, which is independent of the hematocrit rise.

Topics: Adult; Aged; Bleeding Time; Blood Platelets; Endothelium, Vascular; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Recombinant Proteins; Uremia

The purpose of the present study was to investigate the binding of fibrinogen to the platelet fibrinogen receptor. Glycoprotein (GP) IIIa was measured utilizing a fluorescein isothiocyanate (FITC)-labelled monoclonal antibody and an Ortho Spectrum III flow cytometer. The number of binding sites per platelet was calculated to be 30,200. Using this technique it appears possible not only to diagnose Glanzmann's thrombasthenia but also to identify carriers. In uremic patients a slightly lower number of GPIIIa molecules per cell than in control subjects was found. Treatment with erythropoietin had no significant effect on the expression of GPIIIa. Thrombin, and to a less extent ADP, increased the binding of FITC-conjugated fibrinogen to normal platelets but had no significant effect on the expression of GPIIIa.

Topics: Adolescent; Adult; Blood Platelets; Blood Preservation; Erythropoietin; Female; Fibrinogen; Flow Cytometry; Genetic Carrier Screening; Humans; Male; Middle Aged; Platelet Membrane Glycoproteins; Thrombasthenia; Uremia

The effects of increasing amounts of uremic sera (US) on the growth of erythroid progenitor cells [burst-forming unit erythroid (BFU-E)] collected from peripheral blood of normal subjects were evaluated to assess the potential role of uremic inhibitors of erythropoiesis during a treatment with recombinant human erythropoietin (r-HuEpo). US were collected from 8 patients on regular dialysis with marked anemia (Hb 6 +/- 0.5 g%) before and after a treatment with high doses of r-HuEpo (from 300 to 525 U/kg/week). Standard cultures for BFU-E were performed in alpha-metylcellulose with fetal calf serum (FCS) and 4 U/ml of r-HuEpo (Cilag, Ortho). In successive cultures, US were added at increasing amounts to the standard culture in order to assess a possible inhibitory effect on BFU-E growth. Finally, in order to assess a possible lack of stimulatory factors, we partially substituted FCS with US. The addition of US collected either before or after therapy with r-HuEpo to the standard culture had no effect on the growth of BFU-E. Vice versa, the number of cultured BFU-E decreased when FCS was partially substituted with US collected before r-HuEpo. This effect was not evident when FCS was partially substituted with US collected after r-HuEpo. No significant differences were recorded in the tested sera collected before and after therapy considering erythropoietin levels and amino acid levels. We hypothesized that some other factors with erythropoietic stimulatory activity (burst-promoting activity?) may be deficient in uremic patients with marked anemia and can be induced during therapy with r-HuEpo.

Topics: Adult; Anemia; Cells, Cultured; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Growth Inhibitors; Humans; Kidney Failure, Chronic; Recombinant Proteins; Uremia

The aim of this study was to evaluate the effect of r-HuEPO treatment on free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone and prolactin levels in uremic hemodialysis patients. Twenty-four uremic hemodialysis patients were given r-HuEPO with a dose 60 U/kg as intravenous bolus injection at the end of each dialysis session. Once the hematocrit value of the patient had reached a range of 30-35%, the dose was adjusted so as to keep the hematocrit levels constant. Twenty uremic dialysis patients were taken as control group. The above-mentioned hormone levels of patients and control group were determined before and 4 months after r-HuEPO treatment. After the treatment, serum prolactin levels significantly decreased in both sexes (36.8 +/- 7.8 vs 22.9 +/- 6.3 ng/ml and 78.3 +/- 13.3 vs 37.4 +/- 10.4 ng/ml male and female, respectively). FT3 and FT4 significantly increased (1.17 vs 1.67 pg/ml, p < 0.05, and 0.64 vs 0.084 ng/dl, p < 0.05, respectively). TSH levels increased but those changes were not significant. There was no change in the level of any hormone in the control group. Also, the sexual functions of eight male patients treated with r-HuEPO improved and menstruation started again in four female patients. We concluded that r-HuEPO treatment especially decreases prolactin level in uremic hemodialysis patients. It is conceivable that correction of elevated prolactin levels could improve sexual disorders in these patients.

Topics: Adolescent; Adult; Aged; Erythropoietin; Female; Follicle Stimulating Hormone; Hormones; Humans; Luteinizing Hormone; Male; Middle Aged; Prolactin; Recombinant Proteins; Renal Dialysis; Sexual Behavior; Testosterone; Thyrotropin; Thyroxine; Triiodothyronine; Uremia

Topics: Adult; Anemia; Erythropoietin; Female; Hemodynamics; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

We have developed a method for directly estimating the secretion rate of endogenous erythropoietin (EPO) in human subjects. Carrier-free recombinant human EPO was labeled with 125I by the chloramine T method. Human serum albumin was then added prior to removal of free iodide. Seven normal subjects and nine patients with chronic uremia and anemia were studied. Each subject received a bolus of 125I-EPO according to body size and then a constant infusion for 5 h. Secretion rate was calculated as the rate of infusion divided by serum EPO specific activity given by the protein-bound counts divided by the EPO concentration. Serum EPO concentration was significantly higher in the patients than the controls (mean 30.9 pg/ml vs. 11.1 pg/ml, P < 0.05), although all values were within the normal range. Mean EPO secretion rate was 255 in the patients (range 68-1,101) and 190 pg.kg-1 x h-1 in the normal group (range 52-382). This difference was not significant. As the subjects were in a steady state, EPO disappearance/degradation was the same in patients compared with controls despite a relatively hypoplastic marrow.

Topics: Adult; Anemia; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Osmolar Concentration; Reference Values; Uremia

Loss of hypoxic vasodilation has been proposed as a causative factor in the development of hypertension in dialysis patients treated with recombinant human erythropoietin (rHuEPO). Venous occlusion plethysmography was therefore performed on 22 dialysis patients (aged 23 to 71 years, dialysis duration 6 to 260 months, 8 males) before and after correction of anemia with rHuEPO, 50 U/kg 3x/week (Hb: 7.4 +/- 0.3 vs. 10.8 +2- 0.3 g/dl, P less than 0.0001). Hypertension (greater than 15 mm Hg rise in mean BP) occurred in 11 patients. The study was performed while breathing room air and repeated after breathing 60% O2 for 10 to 12 minutes. Before rHuEPO therapy, total blood O2 content increased from 10.01 +/- 0.39 to 10.32 +/- 0.29 ml O2/100 ml blood with breathing 60% O2 (P less than 0.01). After correction of anemia it was 14.65 +/- 0.40 ml O2/100 ml blood on room air (P less than 0.001). There was a significant decrease in forearm blood flow (7.9 +/- 0.5 vs. 6.5 +/- 0.6 ml/min/100 ml tissue, P less than 0.05) and increase in forearm vascular resistance (12.8 +/- 0.1 vs. 16.8 +/- 0.2 mm Hg/ml/min/100 ml tissue, P less than 0.05) with O2 breathing prior to rHuEPO therapy in the blood pressure responders, but no change in these parameters in the group in which blood pressure remained unchanged. When all patients were studied on room air, forearm vascular resistance rose significantly after correction of anemia (13.0 +/- 0.8 vs. 16.3 +/- 0.8 mm Hg/ml/min/100 ml tissue, P less than 0.05), compared with that prior to rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Pressure; Erythropoietin; Female; Forearm; Hemoglobins; Humans; Male; Middle Aged; Oxygen; Recombinant Proteins; Uremia; Vasodilation

This paper describes how Bayesian Networks can be used in combination with compartmental models to plan Recombinant Human Erythropoietin (r-HuEPO) delivery in the treatment of anemia of chronic uremic patients. Past measurements of hematocrit or hemoglobin concentration in a patient during the therapy can be exploited to adjust the parameters of a compartmental model of the erythropoiesis. This adaptive process allows more accurate patient-specific predictions, and hence a more rational dosage planning. We describe a drug delivery optimization protocol, based on our approach. Some results obtained on real data are presented.

Topics: Anemia; Bayes Theorem; Computer Simulation; Drug Therapy, Computer-Assisted; Erythropoietin; Humans; Recombinant Proteins; Uremia

Patients with uraemia have a defect haemostasis caused by severe anaemia and disturbances of platelet/vessel wall interactions. Recombinant human erythropoietin (rHuEPO) treatment not only corrects anaemia, but also shortens the bleeding time. There are few reports dealing with changes of haemostasis during the first month of rHuEPO treatment. We studied platelet function after 1, 2, 4, 8, and 12 weeks of rHuEPO treatment. Erythropoietin was given to 19 dialysed patients with chronic uraemia in a dose of 2000 u subcutaneously 3 times a week. Bleeding time showed a significant fall as early as after the first week of rHuEPO treatment (p < 0.05). After the first month the bleeding time became normal in most of the patients. A significant rise in ristocetin-induced platelet aggregation was observed from the first week of therapy. It showed a strong correlation with the shortening of the bleeding time. Collagen-induced aggregation followed the same pattern but the changes were not striking. There was not significant difference in platelet adhesion, platelet aggregation in the whole blood and those induced by ADP and arachidonic acid. Platelet serotonin concentration was also showed to increase during rHuEPO therapy. We conclude that rHuEPO improves haemostasis by influencing platelet aggregation possibly involving a serotoninergic mechanism but on the other hand may increase a tendency to thrombosis.

Topics: Adult; Anemia; Bleeding Time; Chronic Disease; Erythropoietin; Female; Humans; Male; Middle Aged; Platelet Aggregation; Recombination, Genetic; Renal Dialysis; Uremia

Topics: Erythropoietin; Hemoglobins; Humans; Pruritus; Uremia

Topics: Erythropoietin; Humans; Ketotifen; Pruritus; Uremia

Topics: Erythropoietin; Humans; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Pruritus; Renal Dialysis; Reproducibility of Results; Uremia

The hemostatic effects of recombinant human erythropoietin (rHuEP) were investigated in 20 patients with end-stage renal disease (thirteen on hemodialysis, seven without dialysis) receiving this hormone. We studied their hemograms and coagulation profiles before and at 1 month after initiation of rHuEP therapy. One month after rHuEP administration, improvement in anemia (16/20, 80%) and shortening of bleeding time (17/19, 89.5%) were observed. Shortening or correction of bleeding time was achieved in three patients without any increase of the hemoglobin level. This means that factors other than the increased hematocrit level might contribute to shortening bleeding time in uremic patients receiving rHuEP treatment. The platelet count, prothrombin time, partial thromboplastin time, and fibrinogen level did not change over the course of rHuEP therapy. Thrombosis of vascular access was not observed, and heparin doses were not increased in this short-term period. A significant decrease was found in the plasminogen level, from 108.5% to 88.2% (p less than 0.05), in uremic patients on hemodialysis. The antithrombin III level also decreased, from 98.8% to 89.8% (p less than 0.05), and its level dropped to below normal ranges in six of thirteen patients (46%) on hemodialysis after treatment with rHuEP. No significant change was noted in the levels of antithrombin III, plasminogen, and alpha 2-antiplasmin in uremic patients not receiving dialysis. These results suggest that rHuEP administration induces increased extracorporeal dialyzer clotting and consumption coagulopathy, and that this extracorporeal consumption coagulopathy may play a role in the genesis of thrombotic complications.

Topics: Adult; Aged; alpha-2-Antiplasmin; Anemia; Antithrombin III; Bleeding Time; Blood Coagulation Tests; Chronic Disease; Erythropoietin; Female; Hemoglobins; Hemostasis; Humans; Male; Middle Aged; Peptide Fragments; Plasminogen; Platelet Count; Prothrombin; Recombinant Fusion Proteins; Renal Dialysis; Uremia

Erythrocyte ferritin may be a better estimator of iron bioavailability than the conventional markers of iron stores (serum ferritin and transferrin saturation). To investigate the accuracy of these conventional markers in uremic patients compared with erythrocyte ferritin, we studied 29 chronic hemodialysis patients on erythropoietin (EPO) therapy, 18 without EPO therapy, and 22 healthy control subjects. Apart from the red blood cell indices, serum ferritin, transferrin saturation, and erythrocyte ferritin, the analytical study included red blood cell protoporphyrin and plasma aluminum levels. The control group showed erythrocyte ferritin concentrations between 8.3 and 12.5 attograms/cell (95% confidence interval). In the EPO group, red blood cell protoporphyrin correlated negatively with erythrocyte ferritin, but not with serum ferritin or transferrin saturation. In the non-EPO group, serum ferritin, erythrocyte ferritin, and transferrin saturation did not correlate with red blood cell protoporphyrin. Even though erythrocyte ferritin correlated well with serum ferritin in the EPO group (r = 0.61, P = 0.0003), the sensitivity of normal serum ferritin levels (30 to 300 ng/mL) to discard a low erythrocyte ferritin concentration (erythrocyte ferritin less than 7 ag/cell) was 0.53, while the sensitivity of serum ferritin at levels less than 30 ng/mL to indicate an absolute iron deficiency expressed as a low erythrocyte ferritin concentration was 0.28. Only values of serum ferritin and transferrin saturation greater than 300 ng/mL and 35%, respectively, could rule out a relative iron deficiency expressed as a low erythrocyte ferritin and high red blood cell protoporphyrin concentration. Plasma aluminum levels did not correlate with red blood cell protoporphyrin or erythrocyte ferritin levels in either uremic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia, Hypochromic; Erythrocytes; Erythropoietin; Female; Ferritins; Humans; Iron; Male; Middle Aged; Protoporphyrins; Renal Dialysis; Sensitivity and Specificity; Transferrin; Uremia

Topics: Erythropoietin; Histamine; Humans; Pruritus; Uremia

Topics: Aged; Erythropoietin; Female; Humans; Lipids; Male; Middle Aged; Nutritional Status; Recombinant Proteins; Uremia

Topics: Circadian Rhythm; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Uremia

Improvements in B lymphocyte function have been reported in hemodialysis patients receiving erythropoietin. The present investigation studied whether erythropoietin interferes with B cell function and the mechanisms of this effect. Antibody production by cultured peripheral blood mononuclear cells (PBMC) (7 days) from 15 dialysis patients before and during erythropoietin treatment and from 14 healthy controls was followed. IgG and IgA were formed less in the uremic group than in healthy subjects. After 8 weeks of erythropoietin (hematocrit rose from 19 to 31%) basal IgG formation by PBMC rose from 304 +/- 83 to 566 +/- 49 ng/ml (p less than 0.02), while IgA production rose from 380 +/- 121 to 563 +/- 362 ng/ml (p less than 0.01). IgM production, which appeared to be normal in uremia, remained unchanged during erythropoietin treatment. Production of IgG and IgA stimulated by pokeweed-mitogen was subnormal in uremia, but improved under erythropoietin therapy. To establish whether erythropoietin acted by itself or through correction of the renal anemia, healthy PBMC were directly incubated with 2 U/ml of erythropoietin. Under these conditions production of IgG (+19%), IgA (+28%), and IgM (+32%) was enhanced. Taken together these data indicate a direct stimulant effect of erythropoietin on B lymphocytes in end-stage renal failure.

Topics: Anemia; Antibody Formation; B-Lymphocytes; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Immunoglobulins; Lymphocyte Activation; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

The effect of subcutaneous administration of recombinant human erythropoietin (rHuEPO) on plasma natural coagulation inhibitors (protein C, protein S, and antithrombin III) was evaluated in 10 uremic patients on continuous ambulatory peritoneal dialysis (CAPD). These patients were commenced on a 16 week-course of twice weekly rHuEPO by the subcutaneous route. The hemoglobin increased significantly from 6.9 +/- 1.3 g/dl to 9.6 +/- 1.9 g/dl after subcutaneous rHuEPO treatment (p less than 0.01) at an average dose of 84 +/- 9 U/kg body wt/week. With rHuEPO therapy, a significant increase in platelet counts was observed, albeit within the normal range. A significant increase in the prothrombin time was demonstrated at 6 weeks after treatment and increased activated partial thromboplastin time was observed at 6 weeks and 16 weeks after rHuEPO administration although these measurements still remained in normal range. CAPD patients have comparable or even higher plasma levels of natural coagulation inhibitors compared with healthy controls supporting our previous findings that patients on CAPD have normal plasma levels due to an effective compensatory production despite peritoneal losses of these proteins with CAPD. No change in either the immunological or the functional activity of these natural coagulation inhibitors was demonstrated with rHuEPO therapy and clinical thrombosis was not observed during and after rHuEPO therapy. We conclude that there is no laboratory evidence of increased risk of thrombogenesis due to reduction of natural coagulation inhibitors with rHuEPO therapy.

Topics: Administration, Cutaneous; Antithrombin III; Erythropoietin; Humans; Peptide Fragments; Peritoneal Dialysis, Continuous Ambulatory; Protein C; Recombinant Proteins; Ribonuclease, Pancreatic; Uremia

The present study examined the pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin (SNB-5001) in partially nephrectomized rats. The plasma level of SNB-5001 was measured by a 2-step enzyme immunoassay. The plasma disappearance curve after intravenous injection of SNB-5001 (50 U/kg) in these rats showed a biexponential pattern similar to that in non-treated rats, conforming to a two-compartment model. However, the total body clearance was reduced, the plasma half life was prolonged and the area under the concentration-time curve of SNB-5001 was increased by the partial nephrectomy. The distribution volumes of SNB-5001 were almost the same as those in non-treated rats. It is suggested that the kidney may contribute to the elimination of SNB-5001. Dose-dependent increases of reticulocytes, red blood cells, hemoglobin and hematocrits were observed after seven repetitive intravenous injections of SNB-5001 in both partially nephrectomized rats and non-treated rats. Hemopoietic responses were calculated by subtracting the initial values from the values after SNB-5001 injections of each hematological parameter (reticulocytes, red blood cells, hemoglobin and hematocrits). Hemopoietic responses in partially nephrectomized rats were apparently stronger than those in non-treated rats. These results suggest that the reduction of clearance by the partial nephrectomy may contribute to the hemopoietic responses, in addition to suggesting that the uremic conditions do not inhibit the effects of SNB-5001 in partially nephrectomized rats.

Topics: Animals; Dose-Response Relationship, Drug; Erythropoietin; Half-Life; Hematopoiesis; Kidney; Male; Nephrectomy; Rats; Rats, Inbred Strains; Recombinant Proteins; Uremia

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Intestinal Absorption; Iron; Recombinant Proteins; Renal Dialysis; Uremia

To study the effect of treatment of anaemia with recombinant human erythropoietin (r-HUEPO) on neuromuscular function in patients undergoing haemodialysis for chronic renal failure, six patients were given r-HUEPO in an initial dose of 50 u/kg three times a week and their haemoglobin concentration was measured. The dose was increased by 25 u/kg every four weeks if the response was not satisfactory. In five patients anaemia had been corrected within 12 weeks of initiation of treatment. Neuromuscular function was evaluated before treatment, half way through, and after correction of anaemia by clinical examination and neurophysiological studies including motor nerve conduction velocity, distal latency, electromyography and test for neuromuscular fatigue. After correction of anaemia there was a significant increase in motor nerve conduction velocity, a decrease in the duration of motor unit action potential, and a lessening of neuromuscular fatigue. We conclude that treatment of anaemia with r-HUEPO in patients with chronic renal failure undergoing haemodialysis may improve neuromuscular function.

Topics: Adult; Anemia; Electromyography; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Motor Neurons; Muscle Contraction; Muscles; Neural Conduction; Neuromuscular Diseases; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

Six chronic uremic patients on regular hemodialysis treatment were given recombinant human erythropoietin (r-huEPO) in a dose of 50 U/kg of body weight intravenously thrice weekly for 14 weeks. Following r-huEPO therapy, unstimulated whole blood superoxide anion (O2) generation did not change significantly, while opsonized zymosan-stimulated whole blood O2 generation increased. At the same time, erythrocyte superoxide dismutase and, in particular, glutathione peroxidase activities were found to be reducing with concomitant lowering of erythrocyte malonyldialdehyde (MDA) concentrations and increase in plasma MDA concentrations.

Topics: Adolescent; Adult; Anemia; Antioxidants; Erythrocytes; Erythropoietin; Female; Humans; Male; Recombinant Proteins; Renal Dialysis; Superoxide Dismutase; Superoxides; Uremia

Topics: Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Restless Legs Syndrome; Uremia

The serum concentration of erythropoietin in 79 cases with various blood diseases, uremia, chronic obstructive pulmonary disease etc was determined. At comparable degrees of anemia, patients with myelodysplastic syndrome and aplastic anemia had the highest levels of erythropoietin in our study. The high level of erythropoietin titer in patients with aplastic anemia should be taken as the nom for renal synthesis and release of this hormone. The erythropoietin level in patients with uremic anemia was lower than the level in patients with anemia of other causes but still higher than that of the normal controls. Patients suffering from polycystic kidney disease with or without uremia had a high level of erythropoietin due to local hypoxia of remnant kidney tissue resulting from the pressure of cystic formation. Different methods are used to determine the erythropoietin level, which varies with the stage and etiology of the diseases. There are other stimulating or inhibitory factors of erythropoiesis when the assay is processed. Transfusion and administration of certain drugs also influence the growth of erythroid cells, thus the serum titers of erythropoietin differed markedly between patients at comparable hemoglobin concentration.

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Child; Erythropoietin; Female; Hemoglobins; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Uremia

It has been reported that patients with azotemia have reduced red blood cell (RBC) deformability. Since this is a major determinant of whole-blood viscosity (WBV) and rigid RBCs increase WBV disproportionately relative to the level of hematocrit, it is conceivable that sustained improvement of hematocrit with recombinant human erythropoietin (rhEPO) therapy in azotemic patients might result in abnormally raised WBV. To address this concern, WBV and plasma viscosity (PV) were measured in 9 adult patients (4 men, 5 women) with anemia (mean hematocrit 29.2 +/- 2.7%) and azotemia [mean serum creatinine concentration 339.85 +/- 102.44 mumol/l (3.8 +/- 1.1 mg/dl)] before and after 6 months of treatment with rhEPO (50-175 U/kg given intravenously thrice weekly). Baseline and post-treatment hematocrit, WBV and PV were compared to values derived in 50 normal adult subjects with normal renal function [25 women, 25 men; mean serum creatinine concentration 79.56 +/- 8.84 mumol/l (0.9 +/- 0.1 mg/dl), mean hematocrit 42.4 +/- 3.7%]. To compare rheologic factors at subnormal hematocrits, blood from subjects with normal renal function was diluted with autologous plasma to achieve a range of hematocrits from 20 to 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Viscosity; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Uremia

To clarify the role of chronic anaemia in the pathogenesis of the left ventricular hypertrophy (LVH) of chronic uraemia, nine normotensive dialysed patients were studied before and 3 and 6 months after start of intravenous treatment with recombinant human erythropoietin (rHuEpo). M-Mode echocardiographic estimations of left ventricular mass indices (LVMi) and plasma noradrenaline determinations were made at 3 and 6 months, and total blood volume (TBV) only at 6 months. Resting haemoglobin values were 5.9 +/- 1.3 (SD) g/dl, increased within 3 months to 10.2 +/- 1.2 (P less than 0.001), then remained unchanged. Baseline LVMi was 115 +/- 18 g/m2 body surface area (b.s.a.) and decreased significantly (P less than 0.0025) over the entire period to a final value of 78 +/- 13 g, which did not differ from the average value for 19 healthy controls. Resting plasma noradrenaline was 1.45 +/- 0.44 pmol/ml and did not change significantly, although values were reduced at the 3rd month, when decreased heart rates and slightly and non-significantly increased blood pressures were recorded. TBV did not vary because the increased erythrocyte mass was compensated for by parallel decreases in plasma volume. These data demonstrate the existence of a cause-effect relationship between uraemic anaemia and LVH, although the precise mechanism remains unknown. Amelioration of anaemia with rHuEpo, by allowing recovery from the attendant LVH, might improve long-term cardiovascular prognosis in some dialysed uraemic patients.

Topics: Adult; Anemia; Cardiomegaly; Echocardiography; Erythropoietin; Female; Humans; Male; Middle Aged; Norepinephrine; Renal Dialysis; Uremia

The effect of recombinant human erythropoietin (rHuEPO) on the immune system of hemodialysis patients has been studied by evaluating their response to hepatitis B (HB) vaccination. Fifty hemodialysis patients were given four doses of 20 micrograms recombinant DNA hepatitis B vaccine (SKF) at an interval of 0, 1, 2 and 6 months. Thirty-seven patients could be evaluated at one year. Twelve of 15 (80%) of the rHuEPO treated patients and 12 of 22 (54%) of non-rHuEPO treated dialysis patients developed anti-HBs antibodies. At the time of maximum immune response (8 months), the geometric mean anti-HBs titers (mIU/ml +/- SEM) of responders and all patients were five times (224.0 +/- 5.9 vs. 41.7 +/- 1.5, P less than 0.001), and eight times (57.6 +/- 8.7 vs. 6.7 +/- 1.8, P less than 0.05), respectively, higher in rHuEPO treated patients than in patients not receiving the drug. High antibody response (greater than 100 mIU/ml) prevailed in the group of rHuEPO treated patients and was associated with a high helper/suppressor ratio. Discriminant multivariate analysis (P = 0.038) revealed the influence of treatment with rHuEPO (40%) and helper/suppressor ratio (31%) on antibody concentration, while age, gender, duration of dialysis and previous blood transfusions were similar in both patient groups. Although changes in lymphocyte subsets observed in rHuEPO treated patients may be the result of a reduced administration of blood transfusions, immune reactivity seems also to be directly affected by the drug.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion; Erythropoietin; Female; Follow-Up Studies; Hepatitis B; Hepatitis B Antibodies; Humans; Immune System; Leukocyte Count; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia; Vaccination

We used RNAase protection assays to measure low levels of erythropoietin messenger RNA (EPO mRNA) in the organs of unstimulated rats, and to compare basal and stimulated levels of EPO mRNA in the kidneys and extrarenal organs of rats rendered uremic by subtotal nephrectomy, with pair-fed controls. Using this sensitive assay, EPO mRNA was measured in the kidneys of unstimulated control animals and was detectable, at lower levels, in the liver and lung. After exposure to hypoxia, there was a 150-fold increase in renal EPO mRNA. Hepatic EPO mRNA was also greatly increased and accounted for 39 +/- 10% of the total. The small quantity of EPO mRNA in lung did not increase, but EPO mRNA became detectable in spleen. Animals subjected to subtotal nephrectomy became uremic and anemic (hematocrit 0.32 +/- 0.04 vs. 0.43 +/- 0.04 in controls, P = 0.002), but serum EPO concentrations were not significantly increased (32 +/- 9 vs. 24 +/- 6 mU/ml, P = 0.14). However, after hypoxic exposure, uremic animals increased serum EPO concentrations greatly, although the response was less than in controls (349 +/- 82 vs. 1009 +/- 238 mU/ml, P = 0.002). After hypoxia, extrarenal EPO mRNA levels in uremic animals were similar to controls. In particular, the large hepatic potential for EPO mRNA synthesis was unchanged but accounted for a greater proportion (84 +/- 5%) of the total EPO mRNA. The renal EPO mRNA content was reduced, as expected, after subtotal nephrectomy, but increased 50-fold after hypoxia. In this model of chronic renal failure, despite anemia, a large potential for EPO synthesis exists in liver and remnant kidney.

Topics: Amino Acid Sequence; Animals; Erythropoietin; Hypoxia; Male; Molecular Sequence Data; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger; Tissue Distribution; Uremia

As many as ten patients with terminal uremia on maintenance hemodialysis (MH) performed from 11 to 52 months (28 +/- 4 on the average) were treated with recombinant human erythropoietin (rhERP) manufactured by Cilag (Switzerland). The preparation was injected i.v. in the initial dose 65 U/kg bw thrice a week after each session of MH. If the effect was lacking for 2 weeks, the doze was augmented by 25 U/kg (maximally up to 218 U/kg). Provided the Hb content increased to 100-120 g/l, the maintenance therapy was initiated (108 +/- 13 U/kg). The treatment lasted 17 +/- 2 weeks. As a result, the Hb content in the patients rose from 63.0 to 102.0 g/l, the hematocrit index from 21.2 to 34.4%, the red blood cell count from 2.09 to 3.18 x 10(12)/l; there was a transitory increase of the reticulocyte and platelet counts (from 2.2 to 3.3% and from 172.0 to 284.0 x 10(9)/l) whereas the leukocyte count remained unchanged. It has been demonstrated by the bicycle ergometry data that in addition to the amelioration of the hematological parameters, the patients showed an increase of oxygen consumption at rest, rise of the economy of energy losses at exercise, and a decline of oxygen "cost" of work. According to echocardiography, the patients manifested a reduction of the size of the left heart, of the minute and stroke volumes. In men, the treatment with rhERP brought about libido elevation in the absence of significant alterations in the blood gonadotrophin and testosterone concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Drug Evaluation; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Libido; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Topics: Animals; Calcium; Drug Synergism; Erythrocytes; Erythropoietin; Fishes; Humans; Hypertension; Potassium; Reference Values; Uremia

The ability of blood mononuclear cells (MNC) to produce burst promoting activity (BPA) was evaluated in 31 patients with chronic renal failure. The BPA of cells from uremic patients, with or without hemodialysis, was consistently lower than that of 17 normal donors (mean 64%, P less than 0.01). Coculture of MNC with recombinant erythropoietin (rEpo) in vitro did not increase BPA production. Five of 31 patients received in vivo treatment with rEpo (1,500 units x3/week) and showed therapeutic benefit, but in all patients the BPA production remained low. On the other hand, in four patients who were on a hemodialysis protocol and subsequently underwent renal transplantation, impaired BPA production was resolved quickly, and at the same time the number of circulating BFU-E and the hemoglobin level increased toward normal ranges. Furthermore, such impaired BPA production was not observed in patients receiving continuous ambulatory peritoneal dialysis. These observations suggest that decreased production of BPA may play a role in the development of anemia associated with chronic uremic patients, and the correction of BPA production by the improvement of hemodialysis procedure may result in more effective therapy with rEpo for those patients.

Topics: Adult; Aged; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Transplantation; Male; Middle Aged; Monocytes; Recombinant Proteins; Reference Values; Renal Dialysis; Uremia

Topics: Adult; Aged; Anemia; Blood Pressure; Blood Viscosity; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Topics: Anemia; Animals; Erythropoietin; Kidney Failure, Chronic; Male; Rats; Rats, Inbred Strains; Uremia

Renal anemia is the result of reduced erythropoietin (EPO) biosynthesis in the diseased kidney and also in part the result of a reduced life span of red blood cells (RBCs). An increase in density and a decrease in enzyme equipment (aspartate aminotransferase; GOT) of RBCs reflect cell age. In the following study, the density distribution (median density D50; determined by Percoll density gradients) and GOT activities of RBCs were measured in patients on acetate (HDA; n = 15) and bicarbonate (HDB; n = 51) hemodialysis. Hemoglobin (Hb) concentrations were: in the HDB group, 9.1 +/- 3.4 g/dl; in the HDA group, 6.2 +/- 1.2 g/dl, and, in a control (C) group of healthy persons, 14.0 +/- 1.5 g/dl. 14 HDB patients with severe anemia received EPO therapy during 1 year. D50 were found as follows: group C, 1.0674 +/- 0.0016 g/ml; HDB, 1.0674 +/- 0.0015 g/ml, and HDA, 1.0660 +/- 0.0012 g/ml (HDA vs. group C: p less than 0.05; HDA vs. HDB: p less than 0.05. D50 were elevated in the subgroups of HDA and HDB patients with severe anemia (Hb less than 8 g/dl). During activated erythropoiesis by EPO therapy, D50 decreased from 1.06739 +/- 0.0015 to 1.0656 +/- 0.0014 g/ml. The GOT activities in RBCs demonstrated a rejuvenation of the RBC population in the HDB group (6.4 +/- 2.5 U/g Hb) and HDA group (5.9 +/- 3.1 U/g Hb) compared to group C (3.9 +/- 1.3 U/g Hb).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetates; Acetic Acid; Adult; Aged; Aged, 80 and over; Aspartate Aminotransferases; Bicarbonates; Erythrocyte Aging; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hemodialysis Solutions; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Severity of Illness Index; Sodium; Sodium Bicarbonate; Uremia

The effects of recombinant human erythropoietin (r-HuEPO) on haematological parameters were studied in rats in which uraemia and anaemia had been induced by gentamicin, an aminoglycoside antibiotic and a nephrotoxic agent. After the occurrence of slight polycythaemia, the red blood cell count, haematocrit and haemoglobin concentration decreased by 20-30% compared with those of the control (saline-injected) rats. At the end of gentamicin treatment, the endogenous serum EPO level had decreased to about 40% compared with that of control rats. Gentamicin-treated rats showed marked elevation of blood urea nitrogen, extensive tubular necrosis in the kidney and haemosiderin deposition in the spleen. In the osmotic fragility test, the fragility of erythrocytes significantly increased compared with that of control rats. These findings indicate that the anaemia induced by gentamicin is due not only to a deficiency of EPO but also to an enhancement of fragility of erythrocytes in an azotaemic environment. The administration of r-HuEPO during anaemia markedly increased red blood cell count, haematocrit and haemoglobin concentration. It is suggested that a gentamicin-treated rat is a useful and convenient anaemic model and r-HuEPO is useful for treatment of anaemia in acute renal failure.

Topics: Anemia; Animals; Blood Volume; Erythropoietin; Gentamicins; Hematocrit; Kidney Tubular Necrosis, Acute; Male; Osmotic Fragility; Radioimmunoassay; Rats; Rats, Inbred Strains; Recombinant Proteins; Spleen; Uremia

To obtain information on the effects of the correction of uremic anemia on cardiac function and size, nine normotensive dialyzed patients were studied before, during and six months after the start of i.v. treatment with recombinant human erythropoietin (rHuEPO). Pulsed-doppler echocardiographic determinations of the cardiac index (CI) and M-Mode echocardiographic estimations of the indexed left ventricular end diastolic diameter (LVEDDi), interventricular septum (IVSi), left ventricular posterior wall (LVPWi), with calculations of the left ventricular mass index (LVMi), were made on every occasion. Mean (+/- SD) hemoglobin (Hb) concentration before rHuEPO was 5.9 +/- 1.3 g/dl and rose significantly (p less than 0.0001) up to the third month, then remained constant. Baseline CI (3.4 +/- 0.6 l/min/m2bsa) was significantly higher (p less than 0.0001) than in healthy subjects (2.5 +/- 0.5 l), and decreased after the third month to a value (2.8 +/- 0.5 l) no longer different from that of controls. From pooled baseline and third month data, an inverse relationship between Hb and CI was found (p less than 0.0001). Baseline LVEDDi (32.7 +/- 4.3 mm/m2bsa), IVSi (6 +/- 1.1 mm/m2bsa) and LVPWi (5 +/- 0.8 mm/m2bsa) were all significantly higher than in controls. After three months of therapy, the only change was a decrease in LVPWi while after six months all indices, including the LVMi, decreased to values no longer higher than in controls. From pooled baseline and six months data, an inverse relationship between Hb and LVMi was found (p less than 0.0001). We conclude that treatment of uremic patients by rHuEPO is able to renormalize their already increased cardiac output soon after correction of the anemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Volume; Cardiac Output; Chronic Disease; Echocardiography, Doppler; Erythropoietin; Female; Heart Ventricles; Humans; Male; Middle Aged; Norepinephrine; Recombinant Proteins; Renal Dialysis; Renin; Time Factors; Uremia

The effect of human recombinant erythropoietin (r-EPO) on primary hemostasia was studied in 9 patients undergoing hemodialysis. The analysis was performed before and after the hematocrit reached a value of 30%. The most important complications observed during the study period were a death for acute myocardial infarction in a patient with previous severe ischemic cardiopathy and a thrombosis of the venous line. The bleeding time shortened in four patients although the mean value did not change significantly. Platelet count showed a non significant increase. There was a significant improvement in in vitro platelet aggregability with ADP (p less than 0.05), arachidonic acid (p less than 0.05), adrenaline (p less than 0.05), and ristocetin (p less than 0.05) as well as in the parameters that quantify the interaction between platelets and subendothelium in in vitro experiments using perfused models (p less than 0.05). There were no significant changes in coagulation and fibrinolysis tests. The treatment with r-EPO improved primary hemostasia in uremic patients. This beneficial effect was due to the increased hematocrit and to the improvement of platelet function induced by r-EPO.

Topics: Adult; Aged; Erythropoietin; Female; Hemostasis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Adult; Aged; B-Lymphocytes; Erythropoietin; Female; Humans; Immunoglobulins; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Uremia

Topics: Adult; Erythropoietin; Ferritins; Humans; Iron; Lactoferrin; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Aluminum; Anemia; Deferoxamine; Drug Resistance; Erythropoietin; Humans; Recombinant Proteins; Uremia

Regional peripheral vascular resistance, transcutaneous oxygen pressure and blood pressure were studied in seven normotensive, chronically haemodialysed patients with renal anaemia before and after 3 and 12 months of rHuEpo therapy. Haematocrit increased from 21% to 33% within 3 months of commencing therapy, and remained stable throughout the following observation time. Though regional blood flow of the calf was markedly reduced after 3 and 12 months of rHuEpo compared to pretreatment values, transcutaneous oxygen pressure was significantly increased after 3 months and remained constantly elevated after 12 months. Mean arterial blood pressure increased significantly by 7.3 mmHg after 3 months of rHuEpo treatment but did not reach hypertensive values and was no longer different from pretreatment values 12 months after the start of rHuEpo. Results of peripheral haemodynamic studies were compared to those obtained by measurement of central haemodynamics in four further normotensive anaemic patients. In these patients cardiac output decreased, total peripheral vascular resistance increased and blood pressure increased slightly (by 5.5 mmHg) when a haematocrit of 37% was reached after 8 weeks of rHuEpo therapy. These effects were partly reversed when the maintenance haematocrit decreased to 32% (after 16 weeks of rHuEpo). In summary rHuEpo treatment induced a long-term increase of the total and regional peripheral resistance, an increase of blood pressure within the normal range, and a decrease in cardiac output. Despite these changes tissue oxygenation improved.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hematocrit; Hemodynamics; Humans; Male; Middle Aged; Oxygen; Recombinant Proteins; Uremia

Plasma levels of follitropin (FSH), lutropin (LH) and testosterone (TE) were estimated in 5 anaemic haemodialyzed patients before and after 3 months of erythropoietin treatment (EPO group), in 5 male haemodialyzed patients with a haematocrit value of 33% (which was of the same magnitude as the post-treatment haematocrit value in the EPO group) and in 15 male healthy subjects. After EPO treatment, haematocrit values rose from 23.0 +/- 0.9 to 34.6 +/- 0.75%. EPO treatment induced a significant suppression of basal plasma FSH and LH levels, while plasma TE levels slightly increased. After EPO treatment, the response of plasma FSH and LH to luliberin administration was significantly reduced. As the endocrine profile of EPO-treated patients differed from that of haemodialyzed patients showing a similar haematocrit value, it seems that EPO-induced hormonal changes are not or not only related to improvement of anaemia. Normalization of the pituitary-gonadal feedback in EPO treatment seems to participate in the pathogenesis of improved sexual activity in these patients.

Topics: Adult; Anemia; Erythropoietin; Feedback; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Male; Middle Aged; Pituitary Gland; Renal Dialysis; Sexual Dysfunction, Physiological; Testis; Testosterone; Uremia

Immunoreactive levels of serum erythropoietin (EPO) have been measured in 95 patients with multiple myeloma (MM) and 12 patients with Waldenström's macroglobulinaemia (MW). Of the MM patients 23% were uraemic (mostly light and moderate renal failure) and 61.7% were anaemic. In the anaemic nonuraemic MM patients the mean serum EPO titre was 106.8 +/- 30.4 mU/ml which, when related to the extent of anaemia, was found to be appropriately elevated for the degree of anaemia (the mean haemoglobin (B-HGB) concentration was 6.66 +/- 1.31 mmol/l). The mean serum EPO concentration in uraemic and anaemic MM patients was 39.2 +/- 9.2 mU/ml, which was markedly lower than serum EPO levels in the non-uraemic MM patients, but still higher than in nonanaemic control subjects (22.5 +/- 8.5 mU/ml). The mean B-HGB concentration in uraemic MM patients was 6.04 mmol/l. In the anaemic MM patients with severe renal failure (S-creatinine levels greater than 400 mumol/l) the compensatory secretion of EPO was inadequate in relation to the degree of anaemia. The data indicate that unless the hypoproliferative anaemia of MM is accompanied by considerable renal failure the anaemia does not appear to be associated with a deficient biogenesis of EPO. Likewise the anaemia found in patients with MW also seems, generally, to elicit an appropriate increase in EPO secretion. Reasonably clinically stable MM patients with anaemia and uraemia may be candidates for replacement therapy with recombinant human erythropoietin (rhEPO).

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Multiple Myeloma; Uremia; Waldenstrom Macroglobulinemia

The metabolism of recombinant human erythropoietin (rHuEpo) labelled with 125I has been investigated in five normal and nine 5/6-nephrectomised rabbits. The plasma erythropoietin half-life was significantly prolonged at 5.1 +/- 1.2 h (mean +/- SD) in the 5/6-nephrectomised rabbits, compared to 3.0 +/- 0.4 h in sham-operated controls (P less than 0.001). The disappearance of 125I-labelled rHuEpo is biphasic. Examination of serum by fast protein liquid chromatography (FPLC) following administration of 125I-labelled rHuEpo by FPLC showed a single peak of radioactivity in all rabbits except two of the nephrectomised group. In serum from both of these animals a second labelled peak was found, corresponding to material of MW 200,000-250,000 D. We conclude that the 5/6-nephrectomised rabbit provides a stable model for the study of hormonal metabolism in chronic renal failure.

Topics: Animals; Disease Models, Animal; Erythropoietin; Female; Half-Life; In Vitro Techniques; Male; Nephrectomy; Rabbits; Uremia

Twenty men and 23 women aged from 18 to 65 years, who had been under maintenance haemodialysis for 2 to 16 years and whose haematocrit had been below 30 percent for at least 3 months received recombinant human erythropoietin intravenously at the end of each session for one year. Anaemia was corrected in all patients, the delay in response to each dosage variation being about 4 weeks. The necessary maintenance dosage ranged from 96 to 240 u/kg/week. The number of leucocytes increased significantly until the 4th month, from 5880 +/- 1760 to 6600 +/- 1920 per cubic mm (P less than 0.01). During treatment, pre-dialysis blood creatinine concentrations and potassium and phosphate levels rose, while blood calcium levels fell significantly from 2.45 +/- 0.16 to 2.36 +/- 0.19 mmol/l (P less than 0.01). A nonsignificant increase in systolic and diastolic pressures was also observed, from 129 +/- 16 to 134 +/- 18 mmHg (P = 0.06) and from 75 +/- 9 to 78 +/- 10 mmHg (P = 0.07) respectively. Eight patients (18 percent) required antihypertensive drugs or a higher dose of those previously prescribed. There were 7 cases of vascular thrombosis on pre-existing stenosis, and the dosage of heparin during dialysis had to be increased in most patients. This study confirms that erythropoietin plays a major role in the genesis of the anaemia associated with renal failure. The absence of severe complications in this series was probably due to the criteria of inclusion in the study.

Topics: Adolescent; Adult; Aged; Anemia; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Uremia

In 5 haemodialyzed patients the influence of 3 months' erythropoietin (EPO) treatment on plasma renin activity (PRA), aldosterone (Ald), vasopressin (AVP) and atrial natriuretic peptide (ANP) was studied. Results were compared with those obtained in 7 uraemic patients showing a similar haematocrit value as patients after EPO therapy and with those obtained in 10 healthy subjects. EPO treatment did not influence significantly blood pressure but was suppressing PRA and plasma Ald levels, and raising plasma ANP concentrations. EPO treatment was without influence on AVP plasma levels. Data obtained in this study suggest that EPO-induced endocrine alterations are not due to increased blood volume and only partially related to improvement of uraemic anaemia.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Creatinine; Erythropoietin; Hematocrit; Homeostasis; Hormones; Humans; Male; Middle Aged; Renal Dialysis; Renin; Uremia; Vasopressins

In order to clarify possible factors responsible for varying responses in uremic patients treated with recombinant human erythropoietin (rHuEPO), we determined the inhibitory effects of ten uremic sera on the erythroid progenitors (CFU-E) and erythroid bursts (BFU-E). We also measured plasma EPO titers, Fe, UIBC, ferritin, PTH-C, beta 2-microglobulin, and aluminum in all ten patients. The inhibitor of CFU-E but not BFU-E, was present in the serum of the single anemic patient whose recovery took longer after the administration of rHuEPO. He did not have such conditions as iron deficiency, excess of aluminum, or chronic inflammation. The remaining patients, who had no CFU-E or BFU-E inhibitors, were good responders to rHuEPO. In none of ten patients were there inhibitors of granulocyte-macrophage progenitors (CFU-GM) or any differences in the other parameters. Although the inhibitory factor of CFU-E can be overcome with a larger dose, its prior determination may be useful to set out minimal effective dose of EPO treatment.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Colony-Forming Units Assay; Drug Resistance; Erythropoietin; Female; Granulocytes; Hematopoiesis; Humans; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Renal Dialysis; Uremia

We assessed human recombinant erythropoietin (rHuEPO) as treatment for anemia in azotemic patients who did not require dialytic therapy. The study group consisted of 5 azotemic men and 5 women (mean serum creatinine concentration 5.2 +/- 3.2 mg/dl) whose mean hematocrit was 27.4 + 3.0%. Of these, 5 subjects had diabetic nephropathy. The study was a 12-month rHuEPO maintenance (open label) trial in which a previously established median i.v. dose of 50 U/kg was given three times each week. The rHuEPO was temporarily discontinued when the target hematocrit of 37% was achieved, and after the hematocrit decreased below 35%, it was restarted at half the initial dose. Of the 10 subjects who started the trial, 2 (both nondiabetic) deteriorated early in the study, and before a hematocrit rise was attained commenced maintenance hemodialysis. All subjects completed the year of study and achieved the target hematocrit. Mean hematocrit rose 42% (p less than 0.001) in a mean period of 3.3 +/- 1.3 months. When treatment was interrupted at a hematocrit of 37%, mean absolute reticulocyte count fell from 1.21 +/- 0.59% to 0.38 +/- 0.14% within one week. After rHuEPO was withdrawn, the increase in hematocrit persisted for a mean of 13.0 +/- 6.0 days and patients were able to sustain hematocrits above 35% for a mean of 1.44 +/- 0.6 months. Coincidentally with the rise in hematocrit during rHuEPO treatment, whole-blood viscosity increased significantly (p less than 0.001) but remained within the range for individuals with normal renal function at an equivalent hematocrit (p greater than or equal to 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Viscosity; Diabetic Nephropathies; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia

Recombinant human erythropoietin was administered to 10 uraemic children on chronic haemodialysis, all of whom responded by correcting their haemoglobin. In addition, they showed an increase in blood pressure; platelet aggregations, subnormal before therapy, improved during treatment. The intracellular free calcium concentration in platelets after thrombin stimulation also increased significantly during erythropoietin administration. We hypothesize that the effect of erythropoietin on platelet aggregability and on blood pressure may be due to an increase in the intracellular free calcium mobilisation in platelets and possibly in smooth muscle cells respectively.

Topics: Adolescent; Blood Platelets; Blood Pressure; Calcium; Child; Child, Preschool; Erythropoietin; Female; Humans; Male; Platelet Aggregation; Recombinant Proteins; Uremia

Topics: 2,3-Diphosphoglycerate; Acid-Base Equilibrium; Animals; Diphosphoglyceric Acids; Erythropoietin; Hemoglobins; Hypoxia; Kidney; Rabbits; Uremia

Blood rheology and haemostasis have been investigated in 8 haemodialysis patients during treatment with recombinant human erythropoietin (rHuEPO). The aim was to elucidate the mechanism by which rHuEPO improves haemostasis, and to determine whether rHuEPO promotes intravascular coagulation. Investigations were performed before, and after 3 months of treatment. Haemoglobin and haematocrit rose significantly after rHuEPO (p less than 0.001) and there was a concurrent shortening of the bleeding time. No significant changes were observed in platelet aggregation, thromboxane generation, or platelet nucleotide content during the treatment period. Whole blood viscosity increased following rHuEPO (p less than 0.01), but plasma viscosity and red cell deformability were unchanged, as were markers of intravascular platelet activation and plasma levels of cross-linked fibrin derivatives. No patient suffered from thrombosis during the study period, and elevation of the haematocrit in uraemic patients up to 0.35 with rHuEPO did not appear to lead to intravascular coagulation. Shortening of the prolonged bleeding time in haemodialyzed patients following rHuEPO appeared to be due to the increase in circulating red cells, rather than to changes in platelet reactivity.

Topics: Adult; Bleeding Time; Blood Coagulation; Blood Platelets; Erythropoietin; Female; Hematocrit; Hemostasis; Humans; Male; Middle Aged; Renal Dialysis; Uremia

Conditioned media (CM) of phyto-hemagglutinin-stimulated lymphocytes from chronic uremic patients were studied for burst promoting activity (BPA), using methylcellulose cultures with cord blood cells as a target population. Renal transplantation procedure was followed by a prompt rise of BPA, as well as the number of blood burst-forming unit erythroid (BFU-E) and hemoglobin levels, while no change in BPA and blood BFU-E number was observed in patients receiving rEpo and recovering from anemia. Thus, low BPA secretion from blood cells may have a role in the development of anemia in uremic patients.

Topics: Adult; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Monocytes; Uremia

Topics: Adult; Anemia; Endocrine Glands; Erythropoietin; Hormones; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Renal Dialysis; Renin-Angiotensin System; Uremia

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Uremia

The partial correction of anemia with recombinant human erythropoietin (rHuEpo) is frequently associated with an increase in arterial pressure and could oppose the beneficial effect of anemia correction on myocardial function. In order to analyze the influence of rHuEpo therapy on the vessels and the heart, we performed systemic and regional hemodynamics studies in 11 hemodialysis patients before and 10 to 35 weeks after initiation of rHuEpo therapy, when hemoglobin concentration was 6.8 +/- 0.9 and 10.6 +/- 0.66 g/dl (mean +/- SD), respectively. The mean arterial pressure remained unchanged during this period (88 +/- 21 vs. 88 +/- 15 mm Hg). Echocardiographic study showed that rHuEpo treatment led to a decrease in left ventricular end-diastolic diameter (4.9 +/- 0.5 vs. 5.1 +/- 0.6 cm; P less than 0.03), left atrial diameter (3.22 +/- 0.30 vs. 3.43 +/- 0.33; P less than 0.03), and left ventricular mass index (109.8 +/- 30.6 vs. 133 +/- 30.8 g/m2; P less than 0.05). Left ventricular ejection volume decreased from 86 +/- 24 to 75 +/- 19 ml (P less than 0.03) and heart rate from 76 +/- 9 to 70 +/- 10 beats/min (P less than 0.05). Cardiac index decreased from 4715 +/- 700 to 3635 +/- 444 ml/min/m2 (P less than 0.01) and peripheral resistances rose from 1480 +/- 162 to 1943 +/- 250 dynes.sec.cm-5.m2 (P less than 0.01). Fractional ejection and mean circumferential fiber shortening remained unchanged. The treatment with rHuEpo did not change the aortic diameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anemia; Blood Viscosity; Erythropoietin; Female; Hemodynamics; Humans; Male; Myocardial Contraction; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Uremia

Topics: Adult; Deamino Arginine Vasopressin; Erythropoietin; Female; Hemorrhage; Humans; Uremia

The growth of normal burst-forming units (BFU-E) is known to depend on a burst-promoting activity (BPA) produced by T-lymphocytes. Few BFU-E colonies have been observed in cultures of blood mononuclear cells (MNC) of uremic patients. The aim of the present study was to examine the concentration of BFU-E in the blood of uremic patients and to evaluate the ability of uremic T-lymphocytes to produce BPA. We have studied 6 chronic uremic patients treated with maintenance hemodialysis. When 5 X 10(5) blood MNC depleted of T-lymphocytes of uremic subjects were stimulated by 1 X 10(6) normal T-lymphocytes in a methylcellulose culture system we observed the growth of a number of BFU-E colonies that did not differ significantly from normal (29 +/- 11.8 colonies). On the contrary, when 5 X 10(5) blood MNC depleted of T-lymphocytes of normal subjects were stimulated by 1 X 10(6) T-lymphocytes of uremic patients, the number of BFU-E colonies obtained was significantly lower than normal (1.9 +/- 3.1 colonies). These data show that the decreased number of BFU-E colonies obtained from blood MNC of uremic patients is due to a defect of uremic T-lymphocytes. The impairment of T-lymphocytes can be due to inhibitors of T-lymphocyte function or to variations in T cell subsets, leading to a decrease in the OKT4/OKT8 cell ratio. In any case it is a significant pathogenetic mechanism contributing to anemia in chronic uremia.

Topics: Adult; Chronic Disease; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Male; Middle Aged; T-Lymphocytes; Uremia

Topics: Anemia; Animals; Disease Models, Animal; Erythropoietin; Hematocrit; Hemoglobins; Male; Nephrectomy; Rats; Rats, Inbred Strains; Uremia

Topics: Acute Kidney Injury; Anemia; Animals; Erythropoietin; Humans; Male; Rats; Rats, Inbred Strains; Uremia

Patients with uraemia have a defect of primary haemostasis expressed as long skin bleeding times and reduced platelet adhesion to the arterial subendothelium. Transfusion of red cells shortens the bleeding time and stops bleeding symptoms in uraemia. This study investigated whether the efficacy of recombinant human erythropoietin in correcting anaemia and the improvement in haemostasis are correlated. Recombinant human erythropoietin was given to seven consecutive patients with chronic uraemia, a history of bleeding, severe anaemia (haematocrit below 23%), and long bleeding times (above 19 min). The progressive rise in haematocrit induced by increasing doses of recombinant human erythropoietin was paralleled by a pronounced shortening of the bleeding time. Platelet adhesion to the subendothelium of human umbilical arteries, very low before the study, increased greatly in all patients and became normal in six. None of the patients bled during the study period.

Topics: Adult; Anemia; Erythropoietin; Female; Hematologic Tests; Hemorrhage; Hemostasis; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Fourteen patients with uraemic anaemia and having regular haemodialysis were given human recombinant erythropoietin in increasing doses, beginning with 24 U/kg thrice weekly. One patient was dropped from the study because of recurrent thrombosis of vascular access sites. In the other 13 patients, followed up for a mean of 9.1 months (range 8-11), haemoglobin concentrations increased from 62 (SD 8) to 105 (9) g/l. No antierythropoietin antibodies were detected during the study. The correction of anaemia was associated with a tendency to hyperkalaemia and a mild increase of unconjugated bilirubinaemia. In eight previously hypertensive patients antihypertensive treatment had to be reinforced, but in normotensive patients blood pressure did not change. Thrombosis of arteriovenous fistulas occurred in two patients and a cerebral ischaemic lesion in one. Protracted treatment with human recombinant erythropoietin evidently can maintain normal haemoglobin concentrations in uraemic patients over time. Full correction of anaemia, however, may trigger some vascular problems, particularly in hypertensive patients and those with a tendency to thromboembolism.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Hypertension; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Partially nephrectomized anemic uremic rats were injected with dexamethasone phosphate (10, 50 and 500 micrograms/kg/day), i.p., and erythropoietin (5 U/day), s.c., for 10 days. A marked and usually significant stimulatory effect on erythropoiesis was seen in all uremic animals treated. Administration of erythropoietin and dexamethasone produced a pronounced increment in hemoglobin, hematocrit and circulating reticulocytes. The increase in red blood cell production was also evident through the generally increased absolute numbers of nucleated erythroid cell precursors per milligram of bone marrow. The highest increases were seen in the erythropoietin treated uremic rats. A dose effect correlation was apparent in uremic rats receiving 3 different doses of dexamethasone. Dexamethasone may stimulate erythropoiesis in our anemic uremic rats through a previous augmentation of erythropoietin production in the residual renal mass. A synergistic permissive effect of dexamethasone increasing the sensitivity of the erythropoietin-responsive cells to erythropoietin in bone marrow is also quite possible.

Topics: Anemia; Animals; Bone Marrow; Dexamethasone; Drug Synergism; Erythropoiesis; Erythropoietin; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Stimulation, Chemical; Uremia

Topics: Citrates; Erythropoietin; Gluconeogenesis; Homeostasis; Humans; Inositol; Kidney; Lactates; Mevalonic Acid; Uremia; Vitamin D

Erythropoietin (Epo) titers in various hematological states were determined by a radioimmunoassay. Epo titers in patients with uremic anemia and iron deficiency anemia were inversely correlated with their respective hemoglobin concentrations. Epo titers in patients with uremic anemia were significantly lower than those in patients with iron deficiency anemia with comparable hemoglobin concentrations.

Topics: Anemia; Anemia, Aplastic; Anemia, Hypochromic; Erythropoietin; Humans; Kidney Failure, Chronic; Polycythemia Vera; Renal Dialysis; Uremia

Human recombinant erythropoietin (rHuEPO) has been purified to apparent homogeneity and compared to purified human urinary erythropoietin (EPO). Both the purified natural and recombinant EPO preparations were characterized in a competition radioimmunoassay (RIA), the exhypoxic polycythemic mouse bioassay, in vitro tissue culture bioassays using bone marrow cells, and by Western analysis. In the immunological and biological activity assays, the rHuEPO shows a dose response which parallels that of the natural hormone. By Western analysis, the recombinant and human urinary EPO migrate identically. Administration of rHuEPO increases the hematocrit of normal mice in a dose-dependent manner. Additionally, the rHuEPO is able to increase the hematocrit of rats made uremic as a result of subtotal nephrectomy. In summary, by all criteria examined, the rHuEPO is biologically active and equivalent to the natural hormone.

Topics: Animals; Biological Assay; Bone Marrow Cells; Cells, Cultured; Erythropoiesis; Erythropoietin; Humans; Immunosorbent Techniques; Mice; Radioimmunoassay; Recombinant Proteins; Uremia

The erythropoietin (Ep) plasma titre of 41 anaemic patients with normal renal function or with renal insufficiency (with or without kidney) was measured by RIA and compared to values observed with the polycythaemic mouse assay. A good correlation was found with both methods (r = 0.88). However, about 20% of samples gave higher values with the bioassay. 21 Ep titres measurable by the bioassay ranged from 40 to 4400 mU (mean 717.1 mU) compared to 14.8 to 3788 mU (mean 484.7 mU) measured by the RIA. Low levels of Ep plasma titre have been observed in patients with renal insufficiency and no difference was found between nephric uraemic patients and the anephric group. These results suggest that the increased blood requirements in anephrics are not due to a smaller production of Ep, but ultimately to the presence of an inhibitor of erythropoiesis. The well-known inverse relationship between haematocrit and Ep level was not found in renal insufficiency. However, some humoral regulation of erythropoiesis seems to persist in these patients since the elevation of red blood cells by transfusions was followed by a decrease of the Ep level.

Topics: Biological Assay; Chronic Disease; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Nephrons; Radioimmunoassay; Uremia

delta-Aminolevulinic acid (delta-ALA) synthetase in mouse liver homogenate was significantly (p less than 0.001) higher in the presence of uremic compared with normal plasma, the ratio of the two values being 1.36 +/- 0.24 in 30 paired experiments. This effect does not seem to be due to increased concentrations of urea or creatinine nor to any possible dialyzable substances. Its relationship to the retention of an inducing factor or decreased production of erythropoietin in uremic patients is discussed. A possible inhibitory effect of erythropoietin on liver delta-ALA synthetase is suggested.

Topics: 5-Aminolevulinate Synthetase; Adolescent; Adult; Aged; Animals; Erythropoietin; Female; Heme; Humans; In Vitro Techniques; Liver; Male; Mice; Middle Aged; Uremia

Topics: Blood Proteins; Colony-Stimulating Factors; Erythrocyte Count; Erythropoiesis; Erythropoietin; Humans; Uremia

The relative roles of erythropoietin and potential inhibitors of erythropoiesis in the development of anemia in children with renal disease have been studied. Thirty-five children with renal disease of varied origins and severity were compared with 30 children with anemia of similar severity and with normal renal function. Serum erythropoietin was measured by radioimmunoassay; erythroid (CFU-E) and granulocytic (CFU-GM) progenitor cell growth were assessed in fetal mouse liver cell and normal human bone marrow cell cultures, respectively. The degree of serum inhibition of in vitro CFU-E growth in children with renal disease correlated with both creatinine clearance (r = 0.59, P less than 0.001) and hematocrit level (r = 0.55, P less than 0.005). Serum from children with renal disease inhibited in vitro CFU-E growth in a dose-related manner. Normal serum did not inhibit CFU-E growth in culture. The mean serum erythropoietin concentration was significantly (P less than 0.025) higher in children with anemia of renal disease (32.4 +/- 2.4 mU/ml) in comparison with serum values in normal children (19.6 +/- 1.5 mU/ml), but serum erythropoietin levels did not correlate with hematocrit level, creatinine clearance, or serum inhibition of in vitro erythropoiesis. In contrast, children with anemia and normal renal function showed a significant (P less than 0.001) linear increase in serum erythropoietin concentration (range 28.7 to 327 mU/ml), increased reticulocyte count, and stimulation of CFU-E formation with decreasing hematocrit levels. Coincubation of human urinary erythropoietin in the presence of serum from patients with uremia revealed markedly less immunoreactivity in the radioimmunoassay and less biologic activity in the fetal mouse liver CFU-E assay for erythropoietin than when erythropoietin was incubated with normal human serum, suggesting some alteration of erythropoietin in the presence of uremic serum, which reduced both the immunologic and biologic activity of erythropoietin. Normal and uremic sera inhibited CFU-GM growth to the same degree in comparison with controls. In conclusion, relative erythropoietin deficiency, direct alteration in the biologic activity of erythropoietin by uremic toxins, and serum inhibition of erythroid progenitor cells in the bone marrow are probably important factors in the pathogenesis of anemia in children with renal disease.

Topics: Acute Kidney Injury; Adolescent; Anemia; Animals; Bone Marrow; Child; Child, Preschool; Colony-Forming Units Assay; Creatinine; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Male; Mice; Radioimmunoassay; Renal Dialysis; Stem Cells; Uremia

Homologous erythropoietin (Ep)-rich plasma was infused into sheep to determine the kinetics of this hormone in a large animal model. Ep levels after infusion were measured by radioimmunoassay using a sheep standard. Twenty-seven infusions into normal (14), subtotally nephrectomized (11), and anephric (two) animals were analyzed according to a single-compartment model. The volume of distribution was also calculated, and compared with values obtained indirectly from measurement of chromium 51-labeled red blood cells. The data showed that the t1/2 of the infused hormone was approximately 9 hours and was independent of renal function. After multiple infusions, the t1/2 appeared to shorten. The volume of distribution for this hormone corresponded to the plasma volume of the animals. These studies suggest that Ep, if administered to patients with chronic renal failure, could be given infrequently with little dependence on renal function.

Topics: Anemia; Animals; Erythropoietin; Kidney; Kinetics; Models, Biological; Sheep; Uremia

Topics: Adult; Aged; Anemia; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Kidney Failure, Chronic; Male; Middle Aged; Toxins, Biological; Uremia

The methyl cellulose culture system using human bone marrow and erythropoietin (Ep) at different concentrations was used to examine the effects of uraemic sera on erythropoiesis in vitro. Sera from undialysed patients with advanced uraemia (plasma creatinine greater than 900 mumol/l) when added to cultures at 10% with Ep at 2.0 u/ml were consistently inhibitory to the growth of erythroid burst-forming units (BFU-E). No inhibition of erythroid colony-forming units (CFU-E) was observed at this Ep concentration but inhibition was consistently demonstrated with Ep at 0.2 u/ml. Sera from undialysed patients with less severe uraemia (plasma creatinine less than 900 mumol/l) were not inhibitory to BFU-E or CFU-E at Ep 2.0 u/ml. Sera from patients with stable, functioning renal transplants were stimulatory to erythropoiesis in vitro with Ep at 2.0 u/ml. This finding is consistent with the normal or increased haematocrits often found following renal transplantation. Sera from patients on maintenance haemodialysis and continuous ambulatory peritoneal dialysis (CAPD) were not significantly different from normal in their effect on BFU-E growth in vitro and were slightly but significantly stimulatory to the growth of CFU-E. This suggests that these two forms of dialysis are equally effective in reducing the activity of uraemic inhibitors in serum and that inhibition of the marrow response to Ep and/or burst-promoting activity (BPA) is unlikely to be a major factor in the continued anaemia of dialysis patients.

Topics: Bone Marrow Cells; Cells, Cultured; Erythropoiesis; Erythropoietin; Humans; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia

Extrarenal sites are the major source of erythropoietin (Ep) production in fetuses and neonates. Afterwards, however, the kidneys are the major site. The most likely site of Ep production is the liver, although attempts to extract Ep from the liver have been, to date, unsuccessful. Extrarenal Ep production, as is the case for renal Ep production, is regulated primarily by the oxygen demand: supply. However, some differences have been identified in the response of extrarenal and renal sites of Ep production to several conditions. Two classes of conditions that selectively influence extrarenal Ep production are the subject of this paper. These are the following: 1) factors that cause reparable hepatic injury--including partial hepatectomy, CC14, and bile duct ligation, and 2) continuous perfusion of angiotensin II. The differences between the mechanism by which these two factors influence extrarenal Ep production will be explored and discussed.

Topics: Angiotensin II; Animals; Captopril; Carbon Tetrachloride Poisoning; Colchicine; Erythropoiesis; Erythropoietin; Female; Indomethacin; Kinetics; Liver; Nephrectomy; Organ Specificity; Rats; Rats, Inbred Strains; Uremia

The presence of inhibitors which accumulate during uraemia has been postulated as a significant factor in the development of anaemia in chronic renal failure (CRF). To determine whether factors in uraemic serum depress erythropoiesis, samples were obtained from sheep prior to and after surgical induction of CRF. The sera were tested in vitro for their effect on erythroid colony growth. The sheep sera were substituted for fetal calf serum (30% concentration) in cultures of serotype-matched or autologous sheep marrow cells at optimal doses of erythropoietin (Ep). Forty-two paired sera from five animals were tested against normal (22) and uraemic marrow (20). In 7/42 random pairs, erythroid colony growth was decreased by 20% in the presence of uraemic serum when compared to a normal sample from the same animal. In the remainder of the cultures, uraemic sera stimulated or supported erythroid colony growth as well as normal sera. When the results were analysed individually, serum from only one of five animals showed minimal (10%) in vitro inhibition of erythroid colony growth. This study, performed in a prospective manner utilizing compatible target cells, disputes the hypothesis that uraemic toxins significantly inhibit in vitro erythropoiesis. These data correlate with the in vivo response to Ep in this sheep model, and suggest Ep would be effective in treating the anaemia of CRF.

Topics: Anemia; Animals; Bone Marrow; Cells, Cultured; Colony-Forming Units Assay; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Kidney Failure, Chronic; Prospective Studies; Sheep; Uremia

Topics: Anemia, Hypochromic; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Kinetics; Nephrectomy; Renal Dialysis; Transferrin; Uremia

In patients with chronic renal failure the use of the relatively new dialysis technique of continuous ambulatory peritoneal dialysis (CAPD), unlike other forms of dialysis, is consistently associated with an increase in Hb concentration, but the mechanism remains obscure. We measured Hb, haematocrit, S-erythropoietin and Hb-oxygen affinity in 3 groups of patients with chronic renal failure. (1) Untreated patients starting on haemodialysis. (2) Patients on intermittent peritoneal dialysis changing to CAPD. (3) Patients from the above 2 groups receiving renal transplants. In addition, red cell mass, plasma volume and red cell survival were measured in (2), before starting CAPD and at 6 months. There were distinctly different patterns of change in Hb concentration, Hb-oxygen affinity and S-erythropoietin in the 3 groups of patients. The increase in Hb concentration with CAPD is due to both a fall in plasma volume and an increase in red cell mass, with an increase in red cell survival. There was no change in Hb-oxygen affinity or serum erythropoietin concentration. The improvement in red cell mass and survival may be related to increased clearances of substances with mol. wt.s between 500 and 5000 daltons which accumulate in renal failure (uraemic middle molecules).

Topics: Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Oxygen; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia

Topics: Adolescent; Erythropoiesis; Erythropoietin; Female; Graft Rejection; Hematocrit; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Uremia

This study examined the effect of continuous ambulatory peritoneal dialysis (CAPD) on erythropoiesis and macrophage function. The parameters evaluated were hemoglobin, erythropoiesis-stimulating factor(s) (ESF), and the inhibitory effect of patients' plasma and peritoneal dialysate on erythropoiesis in vitro and on the function of macrophages from normal humans cultured in vitro. ESF was determined by a cell culture assay using hepatic erythroid colony forming cells (CFUE) from newborn mice. The uremic inhibitory effect on macrophages cultured in vitro was expressed as macrophage survival in percentage of controls. Five patients were studied, one of whom was anephric. Hemoglobin increased, without blood transfusions during CAPD treatment, suggesting improved erythropoiesis. Plasma ESF increased in all patients; dialysate ESF increased in all but one patient. Survival of macrophage in vitro, incubated with plasma or dialysate, also improved. In two patients, the inhibitory effect of plasma samples on erythropoiesis in vitro decreased during CAPD treatment. These observations indicate that CAPD removes inhibitors of erythropoiesis and human macrophage function in vitro, and are consistent with transport of inhibitory substances of high molecular weight into the peritoneal cavity. The anephric patient showed improvement of erythropoiesis similar to that of the nephric patients, indicating that the kidney may not be the main producer of erythropoietin (Ep) in patients undergoing CAPD. Peritoneal macrophages may be a site of extrarenal Ep production in this situation. With regard to the parameters studied, CAPD treatment is superior to conventional hemodialysis.

Topics: Adult; Anemia; Colony-Forming Units Assay; Erythropoietin; Female; Hemoglobins; Humans; In Vitro Techniques; Macrophages; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Phagocytosis; Time Factors; Uremia

Chronic renal failure anemia noticeably improves only in patients who undergo CAPD treatment. In order to understand why it is so, the behaviour of some hematological parameters and the weekly clearances of creatinine and peak 7c1 were studied in the course of hemodialysis (HD) and CAPD. Our study shows that an improvement in hematological data is obtained in patients undergoing CAPD but not in those undergoing HD: this result is directly correlated with the increase of the peak 7c1 weekly clearance. Since the serum erythropoietin values are not modified, the improvement of the anemia appears to be related to the reduction of the biochemical abnormality of uremia using a better qualitative or quantitative depuration of bone marrow activity inhibitory material by CAPD.

Topics: Adult; Creatinine; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Reticulocytes; Uremia

Topics: Animals; Dinoprost; Dinoprostone; Erythropoiesis; Erythropoietin; Female; In Vitro Techniques; Mice; Mice, Inbred AKR; Neuraminidase; Prostaglandins E; Prostaglandins F; Radioimmunoassay; Renal Dialysis; Uremia

Dietary restriction of phosphate was found to prevent the development of anemia in partially nephrectomized rats. In an attempt to examine the reason for this beneficial effect, hematologic and nephrologic studies were carried out on normal and on partially nephrectomized rats fed either a normal or a low-phosphate diet. It was first found that a low-phosphate diet ameliorates the degree of renal impairment found four weeks after partial nephrectomy. Nevertheless, it did not eliminate it, and the degree of uremia actually observed should have been associated with a significant reduction in hemoglobin and red cell mass. However, it did reduce serum phosphate and red cell 2,3-diphosphoglycerate (2,3 DPG) levels and increase hemoglobin affinity for oxygen to a degree that should impair oxygen transport to the tissues. That the low phosphate actually caused tissue hypoxia with increased stimulation of the bone marrow was furthermore suggested by the observation that normal rats fed a low-phosphorous diet developed a significant increase above normal in hemoglobin concentration and red cell mass. It was concluded that the effect of a low-phosphate diet on the anemia of uremia is caused by a combination of reduced renal failure and increased tissue hypoxia.

Topics: Animals; Biological Transport; Blood Urea Nitrogen; Creatinine; Diet; Diphosphoglyceric Acids; Erythrocyte Volume; Erythropoietin; Hematocrit; Male; Nephrectomy; Oxygen; Phosphates; Rats; Rats, Inbred Strains; Uremia

Topics: Adrenocorticotropic Hormone; Aldosterone; Angiotensins; Carbohydrate Metabolism; Catecholamines; Endocrine System Diseases; Erythropoietin; Female; Gastrins; Gonadal Steroid Hormones; Humans; Hydrocortisone; Kidney Failure, Chronic; Male; Renal Dialysis; Renin; Thyroid Gland; Uremia; Vasopressins

Topics: Anemia; Animals; Dogs; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Rabbits; Rats; Uremia

Determination of reticulocytes (RETI), haematocrit (HCT) and serum erythropoietin (by radioimmunoassay = EP-RIA) before and after transfusions of 500ml red blood cells (RBC) into 15 chronic uraemic patients demonstrated that there was a converse relation between both of these, EP-RIA and RETI, and the HCT. The same conditions were found in cases of spontaneous bleeding. This pattern of reaction of RETI, EP-RIA and HCT suggested a feedback circuit, operative between these three parameters in chronic uraemic patients.

Topics: Blood Transfusion; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Humans; Radioimmunoassay; Reticulocytes; Uremia

Topics: Animals; Erythropoietin; Glucocorticoids; Heparin; Hydrocortisone; Mercury; Rats; Serum Albumin, Bovine; Trioxsalen; Uremia

The erythropoietin activity and the erythropoiesis inhibiting factor(s) (EIF) were studied in the serum of 10 children and adolescents suffering from terminal renal insufficiency. The influence of haemodialysis on these factors was examined as well. As a test model for the estimation of erythropoietin activity and EIF we used hypertransfused polycythaemic mice. No erythropoietin activity was detectable in the serum of children and adolescents. A 40%-inhibitory effect on erythropoiesis existed in 8 out of 10 uraemic sera prior to dialysis. After haemodialysis the inhibition is eliminated in 4 of the 9 sera examined, and reduced to half in the 5 remaining sera. The findings suggest that the inhibitory effect is possibly caused by one or several EIF of the middle molecule group.

Topics: Adolescent; Animals; Biological Assay; Blood Proteins; Child; Erythropoiesis; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Mice; Renal Dialysis; Uremia

An anephric patient undergoing hemodialysis experienced an increase in his hematocrit value (19 +/- 1 per cent to 31 +/- 1 per cent) as a result of increased erythropoiesis (reticulocyte count 1.8 per cent to 7.4 per cent). This increase occurred in concert with an elevation of the patient's liver enzyme levels and was maintained for four months. The hematocrit value returned to its base line only after the liver function tests showed improvement. During the period when the hematocrit value was increasing, the circulating level of erythropoietin was elavated to 71.0 mU/ml--a level higher than that seen in either anephric or nephric patients undergoing dialysis. When the hematocrit value and liver enzyme levels had returned to their base line values, the erythropoietin level was 4.3 mU/ml--a level in the range seen in anephric patients undergoing dialysis. The observations in this patient suggest that under certain circumstances, the liver can produce erythropoietin in the anephric patient; and, more importantly, that the bone marrow of at least some uremic patients is capable of responding to the endogenous erythropoietin.

Topics: Bone Marrow; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Liver; Male; Middle Aged; Renal Dialysis; Uremia

The commercially available hemagglutination inhibition (HAI) assay kit for erythropoietin (ESF) was compared with the fetal mouse liver cell (FMLC) bioassay. No correlation was obtained ESF levels determined by both methods in a variety of pathologic sera. The HAI kit showed a great batch variability. Significant immunoreactivity was found in those fractions of a normal human serum and a human urinary ESF preparation that were not active in the FMLC bioassay. A very poor recovery of immunoreactivity was found when the international reference preparation for erythropoietin (second IRPE) was added to a normal human serum.

Topics: Absorption; Anemia; Animals; Erythropoietin; Female; Hemagglutination Inhibition Tests; Humans; Liver; Mice; Pregnancy; Sheep; Uremia

Topics: Adult; Anemia; Bone Marrow Examination; Erythropoietin; Female; Humans; Pregnancy; Pregnancy Complications; Uremia

Topics: Adult; Calcitonin; Erythropoietin; Female; Hormones; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prostaglandins; Renal Dialysis; Renin; Testosterone; Uremia

Topics: Anemia; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Hypersplenism; Iron; Kinetics; Renal Dialysis; Uremia

Determinations of immuno-detectable Erythropoietin (idEP), haematocrit (Hct), reticulocyte counts (RC) and serum iron (SI) in uraemic patients with different kidney diseases (KD) and various lengths of chronic haemodialysis treatment (HDT) revealed firstly that all patients had normal idEP, except for analgesic nephropathies who had significantly higher idEP levels; secondly that over six years of haemodialysis idEP increased by about 40% but without concomitant Hct improvement and thirdly that there were no clear interdependencies between Hct, SI, RC and idEP in uraemic patients. In conclusion, inhibitors of erythropoiesis seem to be a major pathogenetic factor in renal anaemia besides a relative deficit in idEP.

Topics: Analgesics; Blood Cell Count; Erythropoietin; Hematocrit; Humans; Iron; Kidney Diseases; Renal Dialysis; Reticulocytes; Time Factors; Uremia

Using the fetal mouse liver cell culture technique for evaluation of erythroid colony formation (CFU-E) sera of 15 patients with CRF and 10 normal subjects were investigated. When sera were removed immediately prior to the onset of regular hemodialysis from patients in a severe uremic state, they produced a significant inhibition of CFU-E formation when tested in the fetal mouse liver cell culture. In contrast, when the same sera after 48 hrs of in vitro dialysis were tested, inhibition of CFU-E formation was reversed to a large part. Inhibition was reversed in the same manner when sera removed from the same patients after 16--20 wks of regular hemodialysis therapy were tested in the fetal mouse liver cell culture. Thus, the EIF present in the serum of patients were severe uremia can be removed by in vivo and in vitro dialysis.

Topics: Anemia; Animals; Cells, Cultured; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Mice; Renal Dialysis; Uremia

Erythropoietin titers were measured in anemic nephric and anephric patients undergoing chronic hemodialysis by utilizing a plasma concentration technique. In eight out of 11 anephric patients studied, decreased but detectable levels of erythropoietin were found, suggesting that extrarenal erythropoietin plays a role in the regulation of red cell production in anephric patients. In 14 nephric uremic patients, erythropoietin production was found to be more variable, with one group of eight patients having erythropoietin levels in the range for normal nonanemic individuals (3.9 to 15 mU/ml), and a second group of six patients with erythropoietin higher than normal (greater than 15 mU/ml). Both groups were found to be equally anemic, indicating that in the second group the bone marrow is less responsive to erythropoietin. The severity of secondary hyperparathyroidism was found to be higher in this second group, suggesting a role of PTH in the bone marrow unresponsiveness. A good correlation between biological and immunological erythropoietin activities was found in the plasma from normal subjects and uremic nephric and anephric patients.

Topics: Animals; Antibodies; Erythropoietin; Female; Humans; Immunoassay; Kidney; Male; Rabbits; Uremia

In the chronic renal insufficiency is shown a decrease as well as an accumulation of some metabolites in the organism. There appear dietarily conditioned insufficiency states and also decreased rates of synthesis of 1,25-OH cholecalciferol , of the renal erythropoietic factor and of histidin. Apart from nitrogenous metabolic end products also the molecules with a middle molecular weight (300-1.500 Dalton) are accumulated. From this, among others, the trade-off hypothesis may be derived, which characterizes the biochemical distrubances in renal insufficiency as a sequel of the accumulation of metabolic regulators. In the analysis of the middle molecule fraction by means of combined chromatographic techniques we succeeded in isolating an inhibitor of glucose utilisation and in defining of some of its biochemical qualities. With the help of this survey the authors demonstrate a new way of thinking and a promising direction for the solution of still unclear probelms of renal insufficiency.

Topics: Amino Acids; Amino Acids, Essential; Dietary Proteins; Erythropoietin; Gluconeogenesis; Humans; Kidney Failure, Chronic; Toxins, Biological; Uremia

Topics: Anemia; Child; Colony-Forming Units Assay; Erythropoietin; Hematopoietic Stem Cells; Humans; Renal Dialysis; Uremia

Topics: Androgens; Anemia; Bone and Bones; Bone Marrow Diseases; Erythropoietin; Estrogens; Female; Folic Acid; Gonadal Steroid Hormones; Hematopoiesis; Humans; Hyperparathyroidism; Kidney; Male; Osteoporosis; Polycythemia; Primary Myelofibrosis; Uremia

Topics: Anemia; Erythropoietin; Humans; Renal Dialysis; Uremia

Topics: Anemia; Animals; Cells, Cultured; Clone Cells; Colony-Stimulating Factors; Creatinine; Erythropoiesis; Erythropoietin; Female; Glycoproteins; Hematocrit; Hematopoietic Stem Cells; Rabbits; Uremia

Studies were performed to determine the effect of injecting repeated doses of erythropoietin (Ep) on the red cell volume of chronically uraemic rats and on that of non-uraemic sham operated ones. After 13 doses of Ep (5 u/dose), started either 5 or 21 d after removal of five-sixths of the renal mass, the increase in the red cell volume of uraemic rats was as great as that of non-uraemic ones. The significance of these results is discussed.

Topics: Anemia; Animals; Erythrocyte Volume; Erythropoietin; Female; Hematocrit; Nephrectomy; Rats; Uremia

To evaluate the role of reduced erythropoietin (Ep) production in the pathogenesis of dialysis anaemia, measurements of serum erythropoietin (SEp) concentration by means of a highly sensitive in vitro bioassay were performed in 88 non-nephrectomised non-transfused regular haemodialysis patients. In 50 patients (group 1) SEp levels were lower than 120 mU/ml. In the remaining 38 patients (group 2) SEp concentrations ranged from 120-369 mU/ml. Group 1 showed a highly significant positive correlation between SEp concentration and haematocrit as did 13 anephric patients investigated for comparison. In contrast, group 2 displayed a highly significant negative correlation between SEp concentration and haematocrit. The results demonstrate the existence of two distinctive groups of similar size in regular haemodialysis patients: those with an absolute (group 1) and those with a relative deficiency of Ep (group 2). In the case of the latter, lack of Ep is probably a secondary factor in the pathogenesis of anaemia, whereas uraemic toxicity and blood loss may play a primary role.

Topics: Anemia; Erythropoietin; Female; Hematocrit; Humans; Male; Renal Dialysis; Uremia

Topics: Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Humans; Kinetics; Uremia

Current concepts of the pathogenesis of anemia in uremic animals are derived mainly from the results of studies performed either in vitro or in bilaterally nephrectomized animals. These data may not be applicable to the situation which exists in more chronically uremic animals. In 1932, Chanutin and Ferris showed that removal of five-sixths of the renal mass caused rats to become uremic and to remain so for a prolonged period of time. Rats made uremic in this manner were utilized as models for studying the pathogenesis of the anemia of uremia. Removeal of five-sixths of the renal mass of rats caused their BUNs to rise to over 100 mg/100 ml and to remain at this level for over 3 wk. The hematocrits of these uremic rats fell from 42% to approximately 30% in 3 wk. Erythropoietin (Ep) production immediately fell to a barely detectable level postoperatively and did not increase significantly in 3 wk, although the renal remnant hypertrophied. Extrarenal Ep production also remained at a low level and did not increase during the 3-wk observation period. The response of plethoric uremic rats to 2 units of Ep was as great (in some experiments greater) as that of sham-operated ones. A surprising finding was that plethoric uremic rats, injected with saline rather than with Ep, incorporated more 59Fe into their red blood cells than did sham-operated ones. This finding suggested that in uremic rats erythropoiesis was less markedly suppressed by plethora than it was in non-uremic rats.

Topics: Anemia; Animals; Blood Urea Nitrogen; Blood Volume; Body Weight; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Injections, Subcutaneous; Iron Radioisotopes; Nephrectomy; Rats; Uremia

Topics: Animals; Erythropoietin; Hemolytic-Uremic Syndrome; Humans; Rabbits; Toxins, Biological; Uremia

In vitro culture technique of bone marrow cells has been applied to study the cause of anemia in uraemic patients on maintenance haemodialysis. Incorporation of 59Fe into haem in bone marrow cells of the patients in the presence of erythropoietin, as well as the inhibitory effect of their plasma on the response of normal bone marrow cells to erythropoietin, was examined. Increase in haem synthesis rate by erythropoietin in the bone marrow cells of uraemic patients (n 14; 7.9 +/- 1.4) wasnot significantly different from that in normal bone marrow cells (n 9; 5.9 +/- 1.4,p greater than 0.05), thus indicating the presence of erythroid precursor cells with normal responsiveness to erythropoetin in uraemic patients. All the plasma from uraemic patients inhibited, in dose-dependent way, the response of normal bone marrow cells to erythropoietin. Levels of erythropoietin in the plasma samples of uraemic patients were much lower than those of the patients with iron deficiency anaemia with comparable Hb concentrations. On the basis of these results, the humoral inhibitory factor appears to play a significant role in the pathogenesis of renal anaemia, in addition to the low level of circulating erythropoietin.

Topics: Adolescent; Adult; Anemia, Hypochromic; Bone Marrow; Bone Marrow Cells; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematopoiesis; Heme; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Uremia

Topics: Adolescent; Adult; Aged; Anemia; Erythropoietin; Female; Hemagglutination Inhibition Tests; Hemorrhage; Humans; Kidney Failure, Chronic; Male; Metrorrhagia; Middle Aged; Uremia

Topics: Adult; Aged; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Renal Dialysis; Uremia

Erythropoietin-responsive stem cell (ERC) kinetics in anephric uremic rabbits were studied in vitro using the growth of erythroid colonies in a methyl cellulose system in cultures with and without the addition of erythropoietin (ESF). Approximately 68 hr after bilateral nephrectomy, an increase in BUN and decreases in hematocrit and marrow erythroid cellularity were seen. However, the numbers of erythroid colonies formed in response to ESF on plates inoculated with 2 times 10-5 cells were greater in anephric rabbit marrows than in normal controls. In addition, the numbers of erythroid colonies produced by the uremic and normal marrows in the presence of ESF were increased in proportion to the number of precursors plated. These findings suggest that, in uremia, the concentration of ERC is increased and that the ERC are capable of responding normally to ESF. The increase in the number of erythroid colonies of uremia may be due to the undisturbed flow of uncommitted hematopoietic stem cells into the ERC compartment in the presence of a delay of differentiation of ERC into heme-synthesizing nucleated erythroid cells due to a lack of ESF.

Topics: Animals; Benzidines; Bone Marrow Cells; Cell Division; Cell Separation; Cells, Cultured; Erythrocytes; Erythropoiesis; Erythropoietin; Nephrectomy; Rabbits; Staining and Labeling; Uremia

Topics: Acute Disease; Erythropoietin; Feeding and Eating Disorders; Heart Failure; Hemorrhagic Disorders; Humans; Hypertension; Peripheral Nervous System Diseases; Renin; Uremia; Vomiting

Topics: Animals; Erythropoietin; Humans; Hypoxia; Kidney; Rabbits; Toxins, Biological; Uremia

Erythropoietic activity produced by exogenous erythropoietin (Ep) is markedly reduced in Swiss mice rendered uremic by bilateral nephrectomy or bilateral ureteral ligation. Exogenous Ep causes a greater increase in erythropoiesis in germfree Swiss mice as compared with non-germfree mice, but the germfree mice show a more drastic reduction of erythropoiesis in uremia. Heme production in blood, spleen, and femoral marrow retains its typical pattern in uremia; there is no shift of erythropoiesis among the three sites. Production of endogenous Ep in uremic mice is less by a factor of 2-3 than that in intact mice whereas the reduction is by a factor of almost 100 in anephric mice. The data suggest that the anemia associated with uremia is the result of two phenomena: (1) a decreased production of Ep and (2) a diminished erythropoietic response to Ep.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Female; Germ-Free Life; Kidney; Male; Mice; Nephrectomy; Uremia

Topics: Anemia, Hypochromic; Arthritis, Rheumatoid; Erythropoietin; Female; Humans; Male; Polycythemia; Polycythemia Vera; Uremia

The effects of sera from anephric rabbits on the rate of heme synthesis in erythroid cells were studied in vitro in rabbit bone marrow cultures. Sera from nephrectomized rabbits significantly (p smaller than 0.05) inhibited 59-Fe incorporation into heme in normal rabbit bone marrow cultures incubated with erythropoietin (ESF) when compared with the response in control culutres with normal serum and ESF. This inhibitory activity increased exponentially with increasing concentrations of the serum in cultures suggesting that a higher concentration of the inhibitor is present in uremia and may be the result of the failure to excrete the inhibitor. This suggests that the retention of this inhibitor may play an important role in the mechanism of the anemia of uremia. The inhibitor of heme synthesis is a low molecular weight substance.

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Erythropoiesis; Erythropoietin; Hematocrit; Heme; Iron; Nephrectomy; Rabbits; Uremia

A highly purified erythropoietin (ESF) preparation (12,000 units per milligram of protein) was labeled with Na'125I using the Chloramine-T method. Undamaged immunoreative labeled ESF was separated from the damaged, nonimmunologically receiveESF by Sephadex G-150 fractionation. This undamaged immunreactive ESF was usedin radioimmunoassay for human erythropoietin. Separation of bound from free antigen was acheived using the double-antibody technique. Approximately 55 per cent binding wasobserved at an antiserum dilution of 1:1500. This assay appears to be sensitive enough to detect as little as 0.025 milliunits of the International Reference Preparation erythropoietin. The estimated levels of thid hormone in normal and anemic uremic human subjects suggests that immunoreactive serum erythropoietin levels are elevated above normal in anemia of uremia.

Topics: Anemia; Animals; Blood Protein Electrophoresis; Chromatography; Dose-Response Relationship, Drug; Erythropoietin; Humans; Iodine Radioisotopes; Isotope Labeling; Rabbits; Radioimmunoassay; Uremia

Bone marrow cells of patients with chronic renal failure were studied in short-term in vitro cultures to determine erythropietin responsiveness. Seven normals and fourtheen patients on hemodialysis were studied. Bone marrow cells of normal subjects and of patients with chronic renal failure responded similarly to erythropoietin. Total heme synthesis was significantly lower in cultures prepared with uremic serum than normal serum. We conclude that there is a substance in the serum of uremic patients which suppresses general heme synthesis and that this "uremic toxin" may be responsible, in part, for the clinically severe anemia seen in these patients.

Topics: Adult; Anemia; Blood Urea Nitrogen; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Erythropoietin; Hematocrit; Heme; Humans; Iron; Kidney Failure, Chronic; Middle Aged; Uremia

Topics: Acute Disease; Acute Kidney Injury; Animals; Erythropoiesis; Erythropoietin; Male; Rats; Uremia

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Survival; Cells, Cultured; Erythrocytes; Erythropoiesis; Erythropoietin; Heme; Humans; Iron; Kidney; Kidney Diseases; Rabbits; Uremia

Topics: Anemia; Animals; Erythrocyte Aging; Erythropoietin; Female; Hematopoiesis; Hemoglobins; Humans; Iron; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Rats; Uremia

Topics: Adaptation, Physiological; Androgens; Anemia; Anemia, Hemolytic; Deficiency Diseases; Diet Therapy; Erythrocytes; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Kidney Failure, Chronic; Nephrectomy; Oxygen Consumption; Renal Dialysis; Uremia; Vitamins

Topics: Animals; Creatinine; Erythropoietin; Hypoxia; Kidney; Ligation; Male; Nephrectomy; Sheep; Time Factors; Urea; Uremia; Ureter

Topics: Anemia; Anemia, Hemolytic; Bone Marrow; Erythropoietin; Hemolysis; Humans; Kidney; Kidney Diseases; Uremia

Topics: Administration, Oral; Adult; Anemia; Blood Transfusion; Blood Urea Nitrogen; Cell Survival; Cholesterol; Creatinine; Erythrocyte Count; Erythrocytes; Erythropoietin; Fluoxymesterone; Hematocrit; Hemoglobins; Humans; Iron; Male; Middle Aged; Plasma Volume; Renal Dialysis; Triglycerides; Uremia

Topics: Adolescent; Adult; Anemia, Hemolytic; Erythropoietin; Female; Hemolytic-Uremic Syndrome; Humans; Kidney Failure, Chronic; Male; Methenolone; Middle Aged; Renal Dialysis; Uremia

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Male; Nephrectomy; Renal Dialysis; Testosterone; Uremia

Topics: Adult; Anemia, Aplastic; Blood Cell Count; Blood Cells; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Reticulocytes; Uremia

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Erythropoietin; Heme; Humans; Rabbits; Uremia

Topics: Animals; Antibodies, Anti-Idiotypic; Erythrocytes; Erythropoietin; Female; Goats; Hypoxia; Iron; Iron Isotopes; Kidney; Ligation; Male; Mice; Nephrectomy; Polycythemia; Rabbits; Rats; Uremia; Ureter

Topics: Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Radioisotopes; Kidney Failure, Chronic; Male; Nephrectomy; Renal Dialysis; Transferrin; Uremia

Topics: Androgens; Blood Urea Nitrogen; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Iron Isotopes; Kidney Diseases; Lymph; Male; Nephrectomy; Pyelonephritis; Renal Dialysis; Testosterone; Thoracic Duct; Uremia

Topics: Animals; Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Humans; Kidney Diseases; Sheep; Uremia

Topics: Adenosine Triphosphatases; Anemia, Hemolytic; Blood Urea Nitrogen; Bone Marrow Cells; Cell Membrane; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Glycolysis; Hemolysis; Humans; Hydrogen-Ion Concentration; Iron; Kidney; Oxygen Consumption; Phosphoric Monoester Hydrolases; Uremia

Topics: Anemia; Blood Transfusion; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Iron Isotopes; Kidney; Kidney Failure, Chronic; Renal Dialysis; Transferrin; Uremia

Topics: Anemia, Aplastic; Animals; Ascites; Blood Transfusion; Chronic Disease; Erythropoietin; Female; Glomerulonephritis; Humans; Hydronephrosis; Immune Sera; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Male; Mice; Phenacetin; Pyelonephritis; Renal Dialysis; Uremia

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Iron Isotopes; Kidney Failure, Chronic; Mice; Polycythemia; Renal Dialysis; Uremia

Topics: Adult; Animals; Bacteria; Child; Culture Techniques; Erythropoiesis; Erythropoietin; Growth; Growth Substances; HeLa Cells; Humans; Lymphocytes; Rabbits; Rats; Uremia

Topics: Adult; Blood Urea Nitrogen; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron Isotopes; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Transplantation Immunology; Transplantation, Homologous; Uremia; Veins

Topics: Adult; Aged; Anemia, Aplastic; Erythropoietin; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Uremia

Topics: Acute Kidney Injury; Aged; Anemia; Animals; Erythropoietin; Female; Haplorhini; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Macaca; Male; Mice; Mice, Inbred Strains; Middle Aged; Uremia

Topics: Animals; Biological Assay; Blood Urea Nitrogen; Cricetinae; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Iron; Iron Isotopes; Kidney; Male; Methods; Punctures; Uremia

Topics: Acute Disease; Adult; Anuria; Blood Cell Count; Blood Transfusion; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Hypertension, Malignant; Male; Nephrectomy; Pyelonephritis; Renal Dialysis; Reticulocytes; Urea; Uremia

Topics: Acute Kidney Injury; Anemia; Animals; Blood Urea Nitrogen; Dogs; Erythropoiesis; Erythropoietin; Female; Humans; Hydronephrosis; Hypoxia; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Mice; Nephrectomy; Peritoneal Dialysis; Polycythemia; Rabbits; Testosterone; Transplantation, Homologous; Uremia

Topics: Anemia; Animals; Biological Assay; Dogs; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Iron; Iron Isotopes; Kidney; Kidney Transplantation; Male; Nephrectomy; Transplantation, Autologous; Uremia

Topics: Amniotic Fluid; Anemia, Aplastic; Animals; Biological Assay; Erythroblastosis, Fetal; Erythrocytes; Erythropoietin; Female; Fetal Diseases; Hemoglobinometry; Humans; Hypoxia; Infant, Newborn; Iron; Iron Isotopes; Maternal-Fetal Exchange; Mice; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Uremia

Topics: Adult; Anemia; Biological Assay; Centrifugation; Electrophoresis; Erythropoietin; Female; Glomerulonephritis; Humans; Infant; Iron Isotopes; Kidney; Male; Plasma; Solubility; Tissue Extracts; Uremia

Topics: Animals; Erythropoietin; Female; Hematocrit; Hemorrhage; Hydronephrosis; Hypotension; Iron Isotopes; Kidney Diseases; Male; Primates; Renal Artery Obstruction; Uremia

Topics: Animals; Erythrocytes; Erythropoietin; Iron Isotopes; Male; Rats; Spleen; Uremia

Topics: Anemia; Erythrocyte Aging; Erythropoietin; Heme; Hemoglobins; Hemolysis; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Metabolic Diseases; Porphyrins; Uremia

Topics: Blood Urea Nitrogen; Bone Marrow; DNA; Epoetin Alfa; Erythropoiesis; Erythropoietin; Iron; Iron Isotopes; Metabolism; Nephrectomy; Pharmacology; Rats; Research; Spleen; Urea; Uremia

Topics: Anemia; Animals; Blood; Epoetin Alfa; Erythropoietin; Haplorhini; Infarction; Ischemia; Kidney Transplantation; Macaca mulatta; Nephrectomy; Research; Thrombosis; Transplantation, Autologous; Uremia

Topics: Absorption; Anemia, Hypochromic; Erythropoietin; Glomerulonephritis; Humans; Iron; Uremia

Topics: Adult; Anemia; Animals; Biological Assay; Blood; Erythropoietin; Female; Hemoglobins; Humans; Male; Mice; Middle Aged; Urea; Uremia

Topics: Anemia; Blood; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Humans; Iron; Kidney Function Tests; Peritoneal Dialysis; Reticulocytes; Uremia

Topics: Anemia; Animals; Blood Volume; Bone Marrow Cells; Chromium Isotopes; Dogs; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hypoxia; Iron Isotopes; Kidney; Nephrectomy; Research; Sheep; Uremia; Ureter

Topics: Blood Platelets; Blood Urea Nitrogen; Bone Marrow Examination; Epoetin Alfa; Erythropoiesis; Erythropoietin; Glomerulonephritis; Hematocrit; Hemoglobinometry; Humans; Hypoxia; Iron; Iron Isotopes; Kidney; Kidneys, Artificial; Leukocyte Count; Male; Nephrectomy; Physiology; Pyelonephritis; Radioisotopes; Radionuclide Imaging; Reticulocytes; Uremia

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Iron; Peritoneal Dialysis; Uremia

Topics: Animals; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematopoiesis; Rabbits; Uremia; Urologic Diseases

Topics: Anemia; Animals; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematopoiesis; Rats; Uremia