losartan-potassium and Renal-Insufficiency

Treatment using the cell sheet technology has been applied to various organs, including the cornea, heart, esophagus, periodontium, cartilage, middle ear, and lungs. It has been shown that the therapeutic efficacy of cell sheet transplantation involves 2 aspects, supplementation of cells and provision of cytokines to the affected organ. In addition, cell sheet transplantation also promotes repair of damage through the paracrine effects of cytokines derived from the transplanted cells. It is known that in cases of cell transplantation by injection, the transplanted cells are less likely to differentiate into renal tissue to supply cells, but repair is promoted by the actions of the transplanted cell-derived renotropic factors. Renal function requires functional conjugation of various tissues, including blood vessels, glomeruli, renal tubules, and collecting ducts. It is difficult to supply the necessary cells directly to the affected site of the renal tissue composed of complex structures. On the contrary, the 2-dimensional cell sheet can produce proteins such as erythropoietin, and is thus suitable for transplantation into the living body. It would be desirable to develop cell sheet therapy for the suppression of kidney damage in the future, taking advantage of the beneficial characteristics of cell sheets.

Topics: Cell Transplantation; Cells, Cultured; Cholecalciferol; Culture Techniques; Cytokines; Erythropoietin; Humans; Kidney; Kidney Diseases; Regeneration; Renal Insufficiency; Stem Cell Transplantation; Tissue Engineering

Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency

Anemia is a disease that is often associated with heart failure (HF) and renal insufficiency (RI). This unfavorable triad of conditions has been called Cardio-Renal-Anemia Syndrome (CRS). The association of HF, RI, and anemia is poorly reported in multicenter clinical trials, so the pathophysiologic mechanisms and treatment options need to be better defined. When CRS patients develop anemia, a "perfect storm" often occurs: HF and RI cause anemia which will worsen the first two conditions. Anemia appears to be the result of complex interactions between cardiac performance, bone marrow homeostasis, renal dysfunction, and various drug side effects. However, neurohormonal and inflammatory activities play a key role in the beginning and progression of the disease. As a consequence, endogenous erythropoietin activity dysfunction with inadequate production and tissue resistance occurs. Despite the advances of therapy in the neurohormonal activation blockade, mortality and hospitalization in HF still remain unacceptably high, suggesting that specific comorbidity treatments could have a significant positive prognostic impact. Anemia should be recognized as one of the novel targets in HF treatment.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Erythropoietin; Heart Failure; Hemoglobins; Humans; Iron; Patient Selection; Prognosis; Renal Insufficiency; Risk Factors; Severity of Illness Index; Syndrome; Water-Electrolyte Balance

In this chapter we want to give an overview on various supportive measures, which help to prevent or to fight complications of multiple myeloma, improve patient wellbeing and increase safety of administration of specific anti-myeloma therapy.

Topics: Anemia; Blood Transfusion; Bone Diseases; Calcitonin; Clodronic Acid; Diphosphonates; Erythropoietin; Fractures, Bone; Hematinics; Humans; Hypercalcemia; Imidazoles; Multiple Myeloma; Osteoporosis; Pamidronate; Recombinant Proteins; Renal Insufficiency; Zoledronic Acid

Among the elderly, anemia occurs with increasing frequency with each advancing decade. Unlike when anemia occurs in younger adults, the cause of anemia in the elderly is oftentimes not readily apparent or attributable to a single cause. However, this commonly observed form of anemia in the elderly (termed unexplained anemia [UA]) can generally be dissected to its root causes, which include renal insufficiency, inflammation, testosterone deficiency, and stem cell proliferative decline. Myelodysplasia (MDS) occurs commonly in this age group but can and should, for both diagnostic and therapeutic considerations, be distinguished from UA.

Topics: Adult; Aged; Aging; Androgens; Anemia; Cellular Senescence; Cytokines; Erythropoietin; Hematopoietic Stem Cells; Humans; Inflammation; Recombinant Proteins; Renal Insufficiency

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Evidence-Based Medicine; Hemoglobins; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Communicable Diseases; Erythropoietin; Evidence-Based Medicine; Hematocrit; Hemoglobinometry; Hemoglobins; Hospitalization; Humans; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Risk Factors; Treatment Outcome

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Topics: Anemia; Drug Resistance; Erythropoietin; Heart Failure; Humans; Renal Insufficiency

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

Nephrogenic systemic fibrosis is a new disorder reported almost exclusively in patients who have renal insufficiency and are exposed to contrast media formulated with gadolinium. High morbidity and mortality are associated with this severely disabling and painful condition. The acute phase begins upon exposure to gadolinium contrast media, characterized by a systemic inflammatory response involving iron mobilization, and then as a progressive, chronic phase in which fibrosis develops. Proposed is a unifying model of cumulative risk factors in which the interplay of systemic inflammation and stimulated hematopoietic environment associated with hyperparathyroidism and erythropoietin may tie to a common pathogenic mechanism of fibrogenesis. Because there are no uniformly effective interventions to treat nephrogenic systemic fibrosis other than successful renal transplantation, prevention by avoiding gadolinium contrast media in patients with chronic kidney disease is vital. On the basis of suspected pathogenesis, it is also reasonable to limit erythropoietin and iron therapy to dosages ensuring recommended targets and adequately control hyperparathyroidism. Herein is reviewed what is currently known about this subject.

Topics: Blood Vessels; Erythropoietin; Fibrosis; Gadolinium; Humans; Inflammation; Iron; Renal Insufficiency

Renal cortical fibroblasts have key roles in mediating intercellular communication with neighboring/infiltrating cells and extracellular matrix (ECM) and maintenance of renal tissue architecture. They express a variety of cytokines, chemokines, growth factors and cell adhesion molecules, playing an active role in paracrine and autocrine interactions and regulating both fibrogenesis and the interstitial inflammatory response. They additionally have an endocrine function in the production of epoetin. Tubulointerstitial fibrosis, the common pathological consequence of renal injury, is characterized by the accumulation of extracellular matrix largely due to excessive production in parallel with reduced degradation, and activated fibroblasts characterized by a myofibroblastic phenotype. Fibroblasts in the kidney may derive from resident fibroblasts, from the circulating fibroblast population or from haemopoetic progenitor or stromal cells derived from the bone marrow. Cells exhibiting a myofibroblastic phenotype may derive from these sources and from tubular cells undergoing epithelial to mesenchymal transformation in response to renal injury. The number of interstitial myofibroblasts correlates closely with tubulointerstitial fibrosis and progressive renal failure. Hence inhibiting myofibroblast formation may be an effective strategy in attenuating the development of renal failure in kidney disease of diverse etiology.

Topics: Animals; Bone Marrow Cells; Cell Communication; Erythropoietin; Fibroblasts; Fibrosis; Humans; Kidney Cortex; Kidney Tubules; Renal Insufficiency; Stromal Cells

Topics: Anemia; Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency

Recombinant human erythropoietin (rHuEpo) has become the most widely used cytokine in the world. Following the success of its use in patients with end-stage renal disease, the usefulness of rHuEpo to ameliorate other anemias was assessed, including pediatric patients and newborn infants. The treatment or prevention of anemia of prematurity with rHuEpo resulted in a significant reduction in the number of transfusions and donor exposure. A clear definition of which premature babies must receive therapy needs yet to be established. Other indications in neonatal period include hyporegenerative and hemolytic anemias. With the exception of chronic renal failure, in older children the efficacy of rHuEpo has not been evaluated as in adults. While an impressive amount of studies were carried out during the last years in adult patients with cancer-related or HIV-infection-related anemias, allowing to establish clear conclusions on its efficacy, only a few trials with small number of patients have been reported in children. Up to date, results in pediatric patients suggest that rHuEpo therapy is as useful as in adult patients, but prospective, randomized trials including large number of patients are essential to achieve definitive conclusions. Results of studies designed to evaluate the efficacy of rHuEpo for sustaining an adequate dose of ribavirin in patients receiving treatment for hepatitis C are encouraging. The potential for use of the non-hematopoietic effects of rHuEpo in newborn infants is a novel and exciting issue. The role of rHuEpo as a tissue protective factor for central nervous system and intestinal mucosa is under exhaustive investigation.

Topics: Adult; Anemia; Anemia, Neonatal; Child; Child, Preschool; Erythropoietin; Hepatitis C; HIV Infections; Humans; Infant; Infant, Newborn; Infant, Postmature; Neoplasms; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Hypertension involves the entire cardiovascular system, and hypertensive vascular disease may promote and exacerbate cardiac and renal dysfunction. We discuss the coexistence of cardiorenal disease as a manifestation of vascular involvement in hypertension, and the relationship of biomarkers of renal vascular involvement in hypertension with cardiovascular endpoints.. Markers of renal dysfunction, especially microalbuminuria, have been considered recently as potent predictors of cardiovascular morbidity and mortality in all explored populations, including hypertensive individuals. Microalbuminuria, per se, is related to vascular injury and to the increased glomerular permeability of albumin as a direct manifestation of renal vascular involvement in hypertension, a systemic vascular disease. Left ventricular hypertrophy in hypertension develops even before proteinuria or impairment of renal function. Factors including anemia, inflammation and hyperuricemia are either induced or exacerbated by renal vascular disease, and each of these may exert additional influence in determining the increased incidence of cardiovascular events with progressive renal dysfunction.. The development and progression of vascular disease is the primary determinant in the progressive cardiac and renal dysfunction observed in hypertension and, therefore, is the underlying mechanism of the overall clinical manifestations of cardiorenal disease. Commonly used biomarkers of renal and vascular function are important tools for determination of the progression and, hence, management of hypertensive disease and its complications.

Topics: Albuminuria; Biomarkers; C-Reactive Protein; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Hyperuricemia; Natriuretic Peptide, Brain; Renal Insufficiency; Uric Acid

Erythropoietin (EPO) has been used widely for the treatment of anaemia associated with chronic kidney disease and cancer chemotherapy for nearly 20 years. More recently, EPO has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of cytoprotective cellular responses, including mitogenesis, angiogenesis, inhibition of apoptosis and promotion of vascular repair through mobilization of endothelial progenitor cells from the bone marrow. Administration of EPO or its analogue, darbepoetin, promotes impressive renoprotection in experimental ischaemic and toxic acute renal failure, as evidenced by suppressed tubular epithelial apoptosis, enhanced tubular epithelial proliferation and hastened functional recovery. This effect is still apparent when administration is delayed up to 6 h after the onset of injury and can be dissociated from its haematological effects. Based on these highly encouraging results, at least one large randomized controlled trial of EPO therapy in ischaemic acute renal failure is currently underway. Preliminary experimental and clinical evidence also indicates that EPO may be renoprotective in chronic kidney disease. The purpose of the present article is to review the renoprotective benefits of different protocols of EPO therapy in the settings of acute and chronic kidney failure and the potential mechanisms underpinning these renoprotective actions. Gaining further insight into the pleiotropic actions of EPO will hopefully eventuate in much-needed, novel therapeutic strategies for patients with kidney disease.

Topics: Erythropoietin; Humans; Renal Insufficiency

Recently there has been considerable interest in the associations between blood hemoglobin (Hb) level, renal function, and cardiovascular disease. Anemia is a common feature of end-stage renal disease, but it also accompanies lesser degrees of chronic kidney disease (CKD). The degree of anemia roughly approximates the severity of CKD. Anemia seen in diabetes has been linked to diabetic nephropathy; however, diabetes itself affects the hematologic system in several ways. Anemia is associated with left ventricular hypertrophy, cardiovascular morbidity, progressive loss of kidney function, and poor quality of life. Anemia seems to act as a mortality multiplier; that is, at every decrease in Hb below 12 g/dL, mortality increases in patients with CKD, cardiovascular disease, and those with both. Unlike blood transfusion, treatment of anemia with exogenous erythropoietin in patients with cardiorenal disease has shown promise in reducing morbidity and in improving survival and quality of life. Increasing the Hb level from less than 10 g/dL to 12 g/dL has resulted in favorable changes in left ventricular remodeling, improved ejection fraction, improved functional classification, and higher levels of peak oxygen consumption with exercise testing. Clinical trials are underway to test the role of erythropoietin in patients with CKD and in patients with heart failure.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Comorbidity; Diabetes Complications; Erythropoietin; Humans; Prevalence; Prognosis; Renal Insufficiency; Risk Factors

Heart failure (HF) is a common disease associated with poor prognosis. Anaemia is commonly associated with HF due to bone marrow depression, reduced availability of iron and haemodilution, and is sometimes aggravated by too frequent blood testing. Low haemoglobin is very detrimental to the haemodynamic state of the patient with decreased cardiac output as it further diminishes the oxygen supply to the tissues. When anaemia is associated with HF. and renal failure, the patient enters a vicious cycle called cardio renal anaemia syndrome. The prognosis of patients with HF is worse as the haemoglobin is lower and even mild anaemia is associated with <1 year survival. Aggressive correction of the anaemia by subcutaneous injections of erythropoeitin and intravenous iron has been shown to improve the functional capacity and quality of life of patients with cardio renal anaemia syndrome and to reduce the need for hospitalization. However, intravenous iron can be detrimental because of increased formation of free radicals, oxidative stress and risk of infection. The level of haemoglobin needed to be achieved is not clear, but it seems indicated to maintain it above 12 g%.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Prognosis; Renal Insufficiency

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation; Renal Insufficiency

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Progression; Erythropoietin; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Neovascularization, Physiologic; Nephritis, Interstitial; Renal Insufficiency

Anemia occurs frequently in chronic heart failure (CHF) patients and is associated with increased morbidity and mortality risk. Clinical trials with recombinant human erythropoietin in patients with chronic kidney disease and concomitant structural heart disease have demonstrated beneficial effects on ventricular remodeling but variable effects on clinical outcome. Preliminary clinical trials in patients with CHF demonstrate that erythropoietin therapy is well-tolerated and associated with short-term clinical benefits. The optimum target hemoglobin, erythropoietin dosing regimen, and role of iron supplementation in patients with CHF are not known. Darbepoetin alfa is a glycosylated derivative of erythropoietin with a prolonged half-life that may allow less frequent dosing in CHF populations. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in CHF patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Humans; Morbidity; Randomized Controlled Trials as Topic; Renal Insufficiency; Treatment Outcome

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Renal Insufficiency

Cardiac disease represents a major cause of morbidity and mortality in dialysis patients, and is also a well-established feature of chronic kidney disease (CKD). Anaemia has also been shown to be a key component not only of dialysis and CKD but also of cardiac disease, including congestive heart failure (CHF). Furthermore, published clinical and laboratory data suggest that anaemia, CHF and CKD are interrelated, each causing the other to worsen and thus resulting in a 'vicious cycle' of disease progression which we have called the Cardio-Renal Anaemia syndrome. In this syndrome anaemia may cause CKD or be caused by CKD, anaemia may cause CHF or be caused by CHF and CHF may cause CKD or be caused by CKD. Numerous publications have borne out the fact that anaemia correction through epoetin treatment provides great benefit to CKD patients. Additionally, there is evidence to suggest that these benefits may be extended to patients with cardiac disease. Uncontrolled and controlled studies of the effect of subcutaneous epoetin treatment in anaemic patients with both CHF and CKD show significant improvements in both cardiac and renal function. Despite these findings, however, it is apparent that anaemia correction is not implemented rigorously within both CHF and CKD populations. Greater awareness of the need for early anaemia correction therapy is therefore required. Cooperation between nephrologists and others who are caring for CHF patients, especially cardiologists, is crucial.

Topics: Anemia; Erythropoietin; Heart Diseases; Humans; Recombinant Proteins; Renal Insufficiency; Treatment Outcome

Anemia is a reduction in the oxygen-carrying capacity of red blood cells that results in a variety of symptoms, including dyspnea, headaches, light-headedness, and fatigue. Although anemia has been associated with reduced health-related quality of life (HRQoL), its treatment has not yet been consistently shown to improve HRQoL.. This systematic review of the literature was conducted to determine whether the treatment of anemia improves HRQoL domains, regardless of the type of underlying disease.. Data for this review were drawn from the clinical trial databases from 2 previous systematic literature reviews of erythropoiesis-stimulating protein treatment for renal insufficiency- and cancer-related anemia, both spanning the period January 1, 1980, through December 31, 2001. MEDLINE, Cancerlit, and Current Contents/Clinical Medicine were searched using the combined terms erythropoietin, kidney failure, neoplasms, and anemia. The reference lists of all identified articles were searched manually for additional relevant papers. The review included prospective studies that reported both HRQoL and hematocrit (Hct) in patients with cancer or renal insufficiency who received treatment for anemia with an erythropoiesis-stimulating protein. HRQoL was categorized by domain (overall, energy/fatigue, physical, activity); changes in HRQoL domains were expressed as effect sizes and meta-analyzed, as were correlation coefficients. The effects on HRQoL of dropout rate, study duration, baseline Hct, and change in Hct were examined in meta-regression analyses.. Sixteen studies each were identified in patients with renal insufficiency (N = 2253) and patients with cancer (N = 10,695). The treated groups included 11,710 patients, and the control groups included 1238 patients. The baseline Hct in all treated groups averaged 26.0%: 28.3% in the group with cancer and 24.4% in the group with renal insufficiency. The mean improvement in Hct from baseline to the end of treatment was 8.3% (range, 1.0%-16.5%) in treated patients and 1.0% (range, 0.0%-3.3%) in controls. The Hct changes were similar in treated patients with cancer and treated patients with renal insufficiency, as was the HRQoL effect size (0.43). Dropout rate and study duration were not significant predictors of HRQoL changes, but change in Hct was a significant predictor in both conditions. Meta-analysis of the correlation coefficients, adjusting for HRQoL domains, showed a consistent and significant positive correlation between change in Hct and change in HRQoL (P < 0.001).. The consistency in both direction and magnitude of effect across many studies and thousands of patients supports the hypothesis that treatment of anemia with erythropoiesis-stimulating protein improves selected HRQoL domains in patients with renal insufficiency- or cancer-related anemia.

Topics: Anemia; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Hematocrit; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Renal Insufficiency; Treatment Outcome

Topics: Androgens; Anemia; Drug Therapy, Combination; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency

Topics: Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Humans; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Insufficiency

The invention of recombinant human erythropoietin (rHuEpo) for the treatment of renal anaemia was a hallmark in the care of patients with renal insufficiency. Recently published guidelines (European Best Practice Guidelines, NKF-DOQI) have set the target haemoglobin to be reached by treatment with rHuEpo to >11 g/dl. Normalizing haemoglobin levels may reduce morbidity and mortality and improve quality of life in haemodialysis patients. During long-term treatment, most patients will not respond adequately to therapy with rHuEpo alone. The most important confounding factor, limiting the effectiveness of rHuEpo, is absolute or functional iron deficiency, which is now recognized and treated in many dialysis units. However, there are several other adjuvant treatment options which may help to optimize the response to treatment with rHuEpo. A weekly dose of 2-3 mg of folic acid and 100-150 mg of vitamin B6 is recommended for haemodialysis patients on rHuEpo therapy. The addition of 0.25 mg/month of vitamin B12 may be necessary in selected patients. Vitamin C (1-1.5 g/week) was shown to overcome functional iron deficiency in patients with high ferritin levels. The potential increase of oxidative stress induced by intravenous iron therapy may be blunted by concomitant administration of vitamin E (1200 IU). There is clear evidence from the literature that treatment of secondary hyperparathyroidism by vitamin D improves erythropoiesis. The most recently discovered biological effects of rHuEpo include the induction of several genes in endothelial cells as well as a role for erythropoietin in the outcome of plasmodium infection. A new erythropoietin-like molecule is novel erythropoiesis stimulating protein (NESP), which is as effective and safe as rHuEpo, with the potential advantage of less frequent dosing.

Topics: Anemia; Chemotherapy, Adjuvant; Endothelium, Vascular; Erythropoietin; Gene Expression Regulation; Humans; Recombinant Proteins; Renal Insufficiency; Treatment Outcome; Vitamins

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

Anaemia is a common problem in patients with renal failure, whether or not they are on dialysis. There is a continuum of declining renal function. In addition, the creatinine clearance at which dialysis is initiated varies widely between institutions and between studies. The term 'progressive renal insufficiency' is therefore preferable to 'pre-dialysis'. The adverse effects of renal anaemia on left ventricular mass become apparent early in the course of progressive renal insufficiency; 75% of patients starting dialysis already have left ventricular hypertrophy (LVH). Correction of anaemia in patients with progressive renal insufficiency has been shown to improve physical function and anaemia-related symptoms, but no controlled studies have yet been conducted to determine its effects on LVH. Although one animal study generated some concern that epoetin may exacerbate a decline in renal function, there is no evidence from human studies for any such effect. Treatment of anaemia with epoetin in anaemic patients with progressive renal insufficiency is therefore recommended, provided blood pressure is controlled. To date, however, there are insufficient data to determine whether normalization of haemoglobin is advisable in this patient group. Detection and correction of iron deficiency is important to achieve the full benefits of epoetin, though recommendations cannot yet be made regarding the optimum route and timing of iron supplementation in patients with progressive renal insufficiency. In these patients the role of other adjuvant therapies, such as L-carnitine, vitamin B6, vitamin B12 and folic acid, also requires further investigation.

Topics: Anemia; Animals; Blood Pressure; Erythropoietin; Hemoglobins; Humans; Iron; Renal Dialysis; Renal Insufficiency

Erythropoietin (Epo) is a glycoprotein produced primarily by the kidney and is the factor regulating the red blood cell production. Unlike most of the hematopoietic growth factors, Epo is principally produced by a single organ, the kidney, and is regulated by a classic feedback control system. Epo acts on the erythroid progenitors after binding to a specific receptor. The gene coding for a 66 Kd chain has been cloned. This chain belongs to the hematopoietic growth factors family. Epo gene was cloned in 1985. The protein coded by this gene is heavily glycosylated. Epo production is regulated by renal tissue hypoxia. Cells producing Epo in the kidney are a subset of peritubular interstitial cells of fibroblastic origin. Epo is now used in clinical applications. Rationale for the use of Epo is based on the serum determination of Epo level. Patients with anemia of chronic renal failure are routinely treated with recombinant Epo. Two other indications are recognized by French authorities: the treatment of anemia of cancer patients receiving platin-derived chemotherapy and the use in autologous blood donation.

Topics: Erythropoietin; Humans; Renal Insufficiency

Erythropoietin, the glycoprotein which regulates erythropoiesis is unique amongst the hematopoietic growth factors since it is the only one which behaves like a hormone. Produced primarily in the kidneys in adults, erythropoietin interacts with erythroid precursors in the marrow to increase red cell production. Because erythropoietin behaves like a hormone, measurements of erythropoietin in the serum have proved useful in determining when production of this hormone is inadequate. Tissue hypoxia is the only physiologic stimulus for erythropoietin production and thus, with anemia, serum erythropoietin levels should be increased. Assuming normal marrow function and adequate nutrient supplies, when anemia is associated with a low serum erythropoietin level, it can be concluded that the anemia is in part due to erythropoietin lack and should be correctable by administration of erythropoietin. As a corollary, a high serum erythropoietin level (greater than 500 mU/ml) in the presence of anemia suggests that there is end organ failure, and erythropoietin therapy is not likely to be useful.

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Humans; Neoplasms; Renal Insufficiency

Erythropoietin (Epo) is a glycoprotein hormone responsible for the control of the proliferation and differentiation of cells of erythroid lineage. Recombinant erythropoietin (rHuEpo) is widely used as a pharmacological agent for the treatment of the anaemia of renal failure. Efficacy of rHuEpo and its superiority over blood transfusions have been proven in large multicentre trials. The most important side-effect of the therapy is the increase of BP which is observed in approximately 30-35% of dialysis patients receiving rHuEpo. It appears that the haemodynamic resetting that occurs with partial correction of anaemia may be inappropriate resulting in an altered vascular resistance in relation to the cardiac output. This is in turn due to the combination of increased blood viscosity and loss of hypoxic vasodilatation. Both these factors, however, cannot account completely for the rise in vascular resistance, and therefore the possibility of a direct and/or hormonally-mediated vasopressor effect of rHuEpo has recently been raised. Moreover, scarce information exists on the possible involvement of endogenous erythropoietin in the pathogenesis of arterial hypertension and haematological disturbances observed in primary and some secondary forms of hypertension.

Topics: Blood Viscosity; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Hypertension; Renal Insufficiency

Topics: Anemia; Erythrocytes; Erythropoietin; Hematopoiesis; Humans; Kidney; Receptors, Erythropoietin; Renal Insufficiency

Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We developed a new ex vivo gene therapy platform called Transduced Autologous Restorative Gene Therapy (TARGT) for sustained long term production and secretion of autologous therapeutic proteins. A biopsy of dermal tissue taken from the patient is transduced ex vivo with a viral vector encoding the required gene under a constitutive promoter. Following measurement of protein secretion ex vivo, the transduced dermal tissue is implanted back into the patient, where it secretes the therapeutic protein into the circulation for several months or longer. A major hurdle to this approach is potential immunogenicity of the transduced tissue following implantation. In this paper we describe the preclinical and early clinical development of this technology, which allowed for overcoming these hurdles. To that end, we have used the helper dependent (HD) adenoviral vector with newly designed expression cassette containing genetic elements to optimize transgene expression. Moreover, we have developed procedures for TARGT tissue implantation, with measures to improve engraftment and reduce inflammation and rejection. Implantation of human TARGT to severe combined immune deficient (SCID) mice indicated long-term production of active proteins in the blood. Preliminary results of a clinical trial from two anemic end-stage renal disease patients, implanted with TARGTs expressing the human erythropoietin (EPO) gene, demonstrated prolonged secretion with physiologic blood level of the hormone and hemoglobin maintenance in the desired range, for a period of at least 5 months without exogenous EPO administration. We believe that the TARGT technology has the potential to become a platform for the sustained delivery of therapeutic proteins in various clinical indications.

Topics: Adenoviridae; Adult; Aged; Animals; Erythropoietin; Genetic Therapy; Humans; Interferon-alpha; Male; Mice; Mice, Inbred NOD; Mice, SCID; Renal Insufficiency; Skin Transplantation

Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.. Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.. In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.. In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses.

Topics: Aged; Anemia; Anti-Inflammatory Agents; Antioxidants; Biosensing Techniques; Cardio-Renal Syndrome; Cluster Analysis; DNA, Complementary; Erythropoietin; Female; Gene Expression Profiling; Heart Failure; Humans; Lipopolysaccharide Receptors; Male; Middle Aged; Monocytes; Oxidative Stress; Renal Insufficiency; Transcriptome

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Topics: Aged; Anemia; Chronic Disease; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Risk; Treatment Outcome

In a one-year, multicenter, open-label, uncontrolled trial, epoetin delta was given subcutaneously, 1-3-times weekly to peritoneal dialysis patients who had previously received an epoetin. Dose was adjusted to maintain hemoglobin at 10.0-12.0 g/dL. The primary endpoint was mean hemoglobin over weeks 12-24. Safety was assessed. Mean+/-SD baseline hemoglobin was 11.2+/-0.9 g/dL. Hemoglobin over weeks 12-24 was 11.6+/-1.1 g/dL. Adverse events were those expected in this patient population. No life-threatening adverse events occurred. Subcutaneous epoetin delta was effective and well tolerated for the treatment of anemia in peritoneal dialysis patients.

Topics: Adult; Aged; Anemia; Animals; CHO Cells; Cricetinae; Cricetulus; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins; Renal Insufficiency

Currently, less frequent than once-weekly subcutaneous epoetin administration regimens were shown to be equally effective and safe as once-weekly schedules in stable predialysis and peritoneal dialysis patients. Bioequivalency of once-every-2-weeks and once-weekly subcutaneous administration of the same total dose of epoetin beta for the maintenance phase of anemia treatment in stable iron-replete long-term hemodialysis patients therefore was investigated prospectively.. Two hundred seven stable selected hemodialysis patients without diabetes, acute illness, significant inflammation, malnutrition or hyperparathyroidism administered once-weekly subcutaneous epoetin beta and preserving stable hemoglobin levels between 10 and 12 g/dL (100 and 120 g/L; difference between maximum and minimum of 3 subsequent levels

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Therapeutic Equivalency; Treatment Outcome

Topics: Adult; Anemia; Erythropoietin; Hematocrit; Humans; Liver Transplantation; Middle Aged; Renal Insufficiency; Treatment Outcome

Patients with renal failure and undergoing hemo- (HD) or peritoneal dialysis are under oxidative stress which is thought to contribute to the long-term complications noted in this patient population. One effect of HD-induced oxidative stress is via red blood cell (RBC) membrane lipid peroxidation leading to RBC destruction and anemia. Interaction of this oxidative stress with epoetin (EPO) treatment to increase RBC number and Hb concentration remains unexplored.. This preliminary study used RT-PCR as well as colorimetric based assay approaches to evaluate the effect of EPO-alpha treatment on markers of oxidative stress in hemodialysis patients. Eighteen patients (12 males, 6 females, age range 45 - 68), were treated with EPO-alpha (Eprex) 50 UI/kg thrice weekly over an 8-month study period. Monocytes were isolated at baseline, then monthly thereafter, monocyte heme-oxygenase-1 (HO-1) and plasma Hb and antioxidant power (AOP) were determined.. Treatment with EPO increased Hb (9.4 +/- 0.7 g/dl to 10.9 +/- 0.5, mean +/- SD p < 0.001). In addition, both monocyte HO-1 mRNA (0.34 +/- 0.08 vs. 0.59 +/- 0.02 d.u. p < 0.001) and plasma AOP (1,379.8 +/- 175 micromol/l to 1,624 +/- 170, p < 0.04) increased. While AOP changes showed no correlation with other indices, increases in HO-1 and Hb were positively correlated using 2 different measures: delta Hb (peak Hb - baseline Hb) vs. delta HO-1 (peak HO-1 mRNA - baseline HO-1 mRNA) as well as delta Hb(5 months-baseline) vs. delta HO-1 (5 months - baseline) mRNA (r = 0.81, p < 0.001 and r = 0.76, p < 0.001; respectively). In conclusion, the increases upon EPO treatment of both HO-1 gene expression and plasma AOP as well as the significant correlation between delta Hb and delta HO-1 mRNA suggest that EPO treatment reduces oxidative stress via a combination of effects. These could potentially include effects on oxidative stress directly as well as effects on the levels and types of antioxidants present in plasma.

Topics: Adult; Aged; Antioxidants; Epoetin Alfa; Erythropoietin; Female; Hematinics; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Male; Membrane Proteins; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Congestive heart failure is extremely common in octogenarians and is associated with severe fatigue, shortness of breath, recurrent hospitalizations, and death. These patients, many of whom are anemic, are often resistant to standard CHF therapy including angiotensin-converting enzyme inhibitors, beta-blockers and diuretics.. To examine whether correction of the anemia (hemoglobin < 12 g/dl) in CHF patients can improve their clinical condition.. Forty octogenarians with anemia and severe resistant CHF were administered a combination of subcutaneous erythropoietin and intravenous iron sucrose.. This combination therapy led to a marked improvement in cardiac function, shortness of breath and fatigue, a marked reduction in the rate of hospitalization and a stabilizing of renal function.. Anemia appears to be an important but ignored contributor to the progression of CHF, and its correction may improve cardiac and renal status as well as the quality of life in elderly patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glomerular Filtration Rate; Glucaric Acid; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Renal Insufficiency; Severity of Illness Index; Time Factors

The ongoing Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) trial is investigating the effect of early anaemia correction in around 600 patients with moderate anaemia [haemoglobin (Hb) 11.0-12.5 g/dl] and chronic kidney disease (CKD) not yet requiring renal replacement therapy (creatinine clearance 15-35 ml/min). Patients are being randomized to early treatment or late treatment with epoetin beta (NeoRecormon) administered subcutaneously. The early treatment group starts epoetin beta therapy immediately, aiming for a target Hb level of 13-15 g/dl. The late treatment group only starts epoetin beta therapy once the Hb level has declined to below 10.5 g/dl (target Hb level 10.5-11.5 g/dl). The objective of the study is to examine the impact of an early anaemia treatment strategy on cardiovascular risk in this patient population. Preliminary baseline data from patients recruited so far indicate there are no clinically relevant differences between treatment groups in terms of their baseline characteristics. The baseline data also confirm the heavy burden in terms of cardiovascular disease present in these patients. The CREATE trial is anticipated to provide important new data that could have an impact on new strategies for management of patients with moderate anaemia and CKD not yet requiring renal replacement therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Risk Factors

To assess the tolerability, safety and efficacy of the epoetin beta multidose cartridge formulation, self-administered subcutaneously via a pen device (Reco-Pen), in adult patients with renal anemia.. Patients receiving maintenance epoetin therapy were switched to the subcutaneous (SC) multidose formulation of epoetin beta (NeoRecormon). The frequency of adverse events, local tolerability, and changes in blood pressure and laboratory variables were recorded. Hematologic parameters, transfusion requirements and epoetin beta dosage were also assessed.. A total of 406 patients were entered in the intention-to-treat analysis. Mean treatment duration was 82.3 days. Fifty patients (12.3%) withdrew from the study; 14 (3.4%) discontinued because of adverse events. Treatment was well tolerated, with adverse events considered probably related to treatment in only 5 cases, and 1 case of local intolerability. There were no clinically significant changes in blood pressure or laboratory variables, and no changes in hematologic parameters or transfusion requirements. Unexpectedly, the epoetin beta dose was reduced by almost one-third in patients previously maintained on SC epoetin.. SC administration of this multidose epoetin beta formulation with the Reco-Pen device was well tolerated and effective. It is possible that the improved capacity to individualize dose may have contributed to the considerable reduction in SC epoetin beta dosage requirement.

Topics: Adult; Aged; Anemia; Blood Transfusion; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Self Administration

Hemodiafiltration (HDF) is associated with a lower incidence of neuropathy, carpal tunnel syndrome, joint pain, and partial correction of anemia. HDF with on-line-prepared substitution fluid (OL HDF), as compared with conventional hemodialysis, increases the treatment tolerance and, as compared with standard HDF, avoids storage problems and allows a higher substitution volume at low cost.. Thirty-two hemodialysis patients treated by OL HDF for at least 9 months were studied. Hemoglobin, hematocrit, iron metabolism, serum albumin, dialysis dose and dry body weight were determined under a settled condition with regular hemodialysis 3 months before the transfer to OL HDF. The same parameters were analyzed 3, 6 and 9 months after the beginning of the new treatment modality.. During OL HDF, hemoglobin values significantly increased in patients without addition of recombinant human erythropoietin (rHuEPO): baseline vs. 6 months 11 +/- 1.7 vs. 12 +/- 1.8 g/dl (p < 0.01); baseline vs. 9 months 11 +/- 1.7 vs. 12 +/- 1.6 g/dl (p < 0.05). In patients on a maintenance dose of rhuEPO, this could be significantly reduced, while the target hemoglobin levels were maintained (10.6 +/- 0.9 g/dl): baseline 99.8 +/- 50.4 U/kg/week, 3rd month 76.2 +/- 43 U/kg/week, 6th month 64.3 +/- 37 U/kg/week, and 9th month 59.4 +/- 38.6 U/kg/week (p = 0.007, p = 0.0006, and p = 0.0007, respectively, vs. baseline). Iron metabolism, dialysis dose, dry body weight and serum albumin levels did not significantly change during the follow-up period. Further, a stability of the rHuEPO supplementation was observed in 14 patients followed up for 24 months.. OL HDF influences anemia and rHuEPO dose. It allows considerable anemia correction in patients without rHuEPO treatment, while it significantly reduces rHuEPO doses in those on rHuEPO treatment as compared with standard hemodialysis. The rHuEPO costs are consequently reduced.

Topics: Adult; Aged; Anemia; Dialysis Solutions; Erythropoietin; Hemodiafiltration; Hemoglobins; Humans; Iron; Middle Aged; Online Systems; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Serum Albumin; Treatment Outcome

To assess the effect of angiotensin-converting enzyme inhibitors (ACEI) on the serum level of erythropoietin (EPO) in patients receiving peritoneal dialysis and explore the possible mechanism.. Thirty-six patients receiving peritoneal dialysis were enrolled in this study, among whom 26 received EPO treatment and the other 10 did not. The 2 groups were randomly subdivided into experimental group and control group with equal cases in each, the former with ACEI prescription to control blood pressure while the latter with calcium channel blocker or alpha-receptor blocker. Serum levels of EPO and hemoglobin (Hb) in all the patients were determined before and 6 months after their respective therapies.. The serum levels of EPO and Hb decreased significantly after therapy in the experimental group (P<0.05), obviously lower than those in the control group (P<0.05).. ACEI may decrease the serum EPO and Hb levels in patients receiving peritoneal dialysis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Hemoglobins; Humans; Peritoneal Dialysis; Renal Insufficiency

Correction of anaemia as a result of renal failure improves cardiovascular function and also provides significant cognitive and emotional benefits. The most appropriate route for iron supplementation has not been determined for patients with chronic renal failure who are not yet on dialysis.. Forty-five anaemic patients with progressive renal insufficiency (PRI) were prospectively randomized to receive oral (ferrous sulphate 200 mg tds) or intravenous (300 mg iron sucrose monthly) iron treatment. Erythropoietin (rHuEpo) was simultaneously commenced and the dose adjusted according to a pre-established protocol.. There were no significant differences in baseline patient characteristics between the two groups. The average follow-up was 5.2 months. Three patients suffered possible allergic reactions to iron sucrose. Haemoglobin response and changes in red cell hypochromasia were similar in the two groups, but serum ferritin was significantly higher in the intravenous group. The starting dose of rHuEpo could be temporarily discontinued in 43% of patients on oral iron and 33% of patients receiving iron sucrose (NS). rHuEpo was increased after 3 months in 9% of patients on oral iron and 19% of patients receiving iron sucrose (NS). Final doses of rHuEpo were 33.5 (0-66) and 41.6 (0-124) U/kg/week respectively in the oral and intravenous groups (NS). Although gastro-intestinal symptoms were more commonly reported in patients taking oral iron, these were mild according to scores on visual analogue scales. Dietary protein and energy intake were not significantly different in the two groups at 0, 3 and 6 months.. In pre-dialysis patients, the efficacy of monthly 300 mg iron sucrose given intravenously is not superior with regard to haemoglobin response and rHuEpo dose as compared with a daily oral dose of 600 mg of ferrous sulphate or equivalent. Where intravenous iron is preferred, lower doses may help to reduce the incidence of allergic or "free iron" reactions, especially in patients with low body mass.

Topics: Administration, Oral; Aged; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Ferrous Compounds; Gastrointestinal Diseases; Glucaric Acid; Hemoglobins; Humans; Injections, Intravenous; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency

Topics: Adult; Anesthetics, Local; Child; Drug Compounding; Erythropoietin; Female; Humans; Injections, Subcutaneous; Lidocaine; Lidocaine, Prilocaine Drug Combination; Male; Pain; Prilocaine; Recombinant Proteins; Renal Insufficiency

In 16 patients (9 on azathioprine, 7 not) the ineffective iron turnover (IIT) was much higher in the azathioprine group (62.7 +/- 6.7 vs. 23.5 +/- 3.5 mumol/l blood/day, p < 0.0001, 2-tailed t test), though the red cell iron turnover (RCIT) was similar (42.8 +/- 2.9 vs. 41 +/- 4.8). Erythropoietin improved the anaemia in all patients and raised the RCIT (4 still on azathioprine to 72.2 +/- 9.8, p < 0.003; 7 non-azathioprine patients to 62.7 +/- 5.3, p < 0.01); the IIT remained higher in the azathioprine-treated (85.5 +/- 19.3 vs. 37.1 +/- 5.4; p < 0.013). In 2 patients who discontinued azathioprine, the IIT declined markedly to normal. In summary, azathioprine exacerbates the anaemia of renal failure by augmenting ineffective erythropoiesis, while erythropoietin benefits those on azathioprine as much as other renal patients by stimulating both effective and ineffective erythropoiesis.

Topics: Anemia; Azathioprine; Bone Marrow; Drug Interactions; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Male; Recombinant Proteins; Renal Insufficiency

Eight young children with renal failure, undergoing continuous peritoneal dialysis (CDP) and presenting an anemia (hemoglobin level [Hb] 57 to 89 g/l) were treated by subcutaneous recombinant human erythropoietin (rHu EPO) twice weekly. The initial dose of 75 U/kg was adjusted to induce progressive increase of Hb with a target level of 100-120 g/l. Treatment duration was 24 weeks in five of these children and 10 to 13 weeks in the three others. In seven cases out of eight, anemia was corrected. The target Hb level was reached in 3 to 21 weeks with rHu EPO doses of 150 to 300 U/kg/w (mean: 200 U/kg/w) for four children without recent transfusion; then the median maintenance dose was 135 U/kg/w (range: 50-300 U/kg/w). In only one patient, Hb never reached a level higher than 77 g/l despite weekly dose of 350 U/kg, a reticulocytosis of 5.6%, rHu EPO treatment lasting up to 24 weeks and the absence of iron deficiency. In any case, no transfusion was necessary after the first day of rHu EPO treatment. In three patients, the increase of a preexisting hypertension required the adaptation of antihypertensive treatments. One patient presented a marked thrombocytosis. In conclusion, twice-a-week subcutaneous injections of 75 to 150 U/kg of rHu EPO appear to be well tolerated and effective in the treatment of anemia of CPD children.

Topics: Anemia; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Insufficiency

Chronic kidney disease involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Disease Models, Animal; Erythropoietin; Ferritins; Fibrosis; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Iron Regulatory Protein 1; Kidney; Male; Mice, Inbred C57BL; Mice, Knockout; Procollagen-Proline Dioxygenase; Receptors, Transferrin; Renal Insufficiency; Ureteral Obstruction

Erythropoiesis-stimulating agents (ESAs) and iron supplements may be prescribed appropriately under nephrology care. However, there are few reports detailing the differences in prescription rates of these therapies among clinical departments.. The lower the eGFR, the more the number of patients seen under nephrology care. The rates of patients with no prescription were 52.3, 39.9, 45.9, and 54.3% among those with hemoglobin levels of < 8, 8 ≤  < 9, 9 ≤  < 10, and 10 ≤  < 11 g/dL, respectively. Of the patients with less than 11.0 g/dL of hemoglobin, 77.3% were prescribed ESAs under nephrology care. Meanwhile, only 18.5 and 8.2% of patients were prescribed ESAs in clinical departments of internal medicine, other than nephrology, and non-internal medicine care, respectively.. Treatment for anemia has not been sufficiently performed in patients with renal impairment under non-nephrology care in a real-world clinical setting.

Topics: Academic Medical Centers; Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Japan; Nephrology; Prescriptions; Renal Dialysis; Renal Insufficiency

Anemia is a common complication in patients with renal failure. While erythropoietin is commonly used to treat anemia, some patients exhibit a poor response to erythropoietin. Since store-operated calcium channel (SOC) signaling is one of the erythropoietin activated pathways, we aimed to investigate the association between the genetic polymorphisms of SOC signaling pathway and erythropoietin resistance in patients with renal failure.Four tagging single nucleotide polymorphisms in STIM1 and five in ORAI1 were selected in this study. Genotyping was performed with the TaqMan Allelic Discrimination assay and the association of individual tagging single nucleotide polymorphisms with erythropoietin resistance was analyzed by multivariable adjusted random intercepts model.194 patients were enrolled in this study. The mean age of participants is 68 years, and 56% were men. The mean erythropoietin resistance index was 9.04 ± 4.51 U/Kg/week/g/dL. We found that patients with the AA genotype of rs1561876 in STIM1, and the CC or CT genotypes of rs6486795 in ORAI1, were associated with increased risk of erythropoietin resistance. Functional annotation of expression quantitative trait loci revealed that the AA genotype of rs1561876 in STIM1 has a relatively lower expression of ribonucleotide reductase catalytic subunit M1 in skeletal muscle, while the CC genotype of rs6486795 in ORAI1 has a relatively higher expression of ORAI1 in the whole blood and thyroid.Overall, we demonstrate a significant association between erythropoietin resistance and genetic polymorphisms of STIM1 and ORAI1. Annotation prediction revealed the importance of SOC-mediated calcium signaling for erythropoietin resistance.

Topics: Aged; Calcium Signaling; Drug Resistance; Erythropoietin; Female; Humans; Male; Middle Aged; Neoplasm Proteins; ORAI1 Protein; Pharmacogenomic Variants; Renal Insufficiency; Stromal Interaction Molecule 1

Clinical studies have shown that treatment with inhibitors of sodium-glucose cotransporter 2 (SGLT2) significantly increases the hematocrit in patients with type 2 diabetes. To investigate whether SGLT2 inhibitors directly promote erythropoietin production independently on blood glucose reduction, the hematopoietic effect of the specific SGLT2 inhibitor, luseogliflozin, was examined in non-diabetic rats with renal anemia.. Renal anemia was induced by treatment with adenine (200 or 600 mg/kg/day, orally for 10 days) in non-diabetic Wistar-Kyoto or Wistar rats, respectively. Luseogliflozin (10 mg/kg bodyweight) or vehicle (0.5% carboxymethyl cellulose) was then administered for 6 weeks. The hematocrit and the hemoglobin (Hb), blood urea nitrogen, plasma creatinine, and plasma erythropoietin levels were monitored.. Treatment with adenine decreased the hematocrit and the Hb level, which were associated with increases in the blood urea nitrogen and plasma creatinine levels. In Wistar-Kyoto rats treated with 200 mg/kg/day adenine, administration of luseogliflozin induced glycosuria, but did not change the blood urea nitrogen, plasma creatinine levels, hematocrit, Hb or plasma erythropoietin levels. Similarly, luseogliflozin treatment failed to change the hematocrit or the Hb levels in Wistar rats with renal anemia induced by 600 mg/kg/day of adenine. Plasma erythropoietin concentrations were also not different between luseogliflozin- and vehicle-treated rats. Similarly, in human erythropoietin-producing cells derived from pluripotent stem cells, luseogliflozin treatment did not change the erythropoietin level in the medium.. These data suggest that SGLT2 inhibitor fails to exert hematopoietic effects in non-diabetic conditions.

Topics: Adenine; Anemia; Animals; Disease Models, Animal; Erythropoietin; Hematocrit; Hematopoietic Stem Cells; Hemoglobins; Humans; Kidney; Male; Rats; Rats, Inbred WKY; Rats, Wistar; Renal Insufficiency; Sodium-Glucose Transporter 2 Inhibitors; Sorbitol

A 47-year-old female patient presented nausea and vomiting for half a year and elevated serum creatinine for 3 days. Proximal renal tubular acidosis (RTA) complicated with anemiawas confirmed after admission. Secondary factors, such as autoimmune disease, drugs, poison, monoclonal gammopathy, were excluded. Renal biopsy revealed acute interstitial nephritis. The patient was administrated with daily prednisone 50 mg, sodium bicarbonate 4 g, 3 times per day, erythropoietin 3 000 U, 2 times per week, combined with potassium, calcium, and calcitriol tablets. Serum creatinine reduced to 90 μmol/L. However nausea and vomiting deteriorated with lactic acidosis. Bone marrow biopsy indicated the diagnosis of non-Hodgkin lymphoma, therefore the patient was treated with chemotherapy. Although metabolic acidosis improved gradually after chemotherapy, severe pneumocystis carinii pneumonia developed two weeks later. The patient refused further treatment and was discharged.. 患者女性，47岁。因恶心、呕吐半年，发现肾功能异常（血肌酐255 μmol/L）3 d就诊，入院检查发现近端肾小管酸中毒合并贫血，排除自身免疫病、药物、毒物、单克隆免疫球蛋白病等继发因素，肾脏穿刺活检组织病理提示急性间质性肾炎，予泼尼松50 mg/d；碳酸氢钠4 g，3次/d；促红细胞生成素3 000 U，2次/周；氯化钾缓释片500 mg，3次/d；碳酸钙500 mg，3次/d；骨化三醇0.5 μg，1次/d。患者血肌酐恢复至90 μmol/L，但随诊期间患者恶心呕吐加重，再次检查发现合并乳酸酸中毒（乳酸14.1 mmol/L）。骨髓穿刺提示非霍奇金淋巴瘤，予CHOP方案化疗，期间乳酸酸中毒逐步好转（乳酸由14.5 mmol/L降至3.1 mmol/L），半个月后发生重症耶氏肺孢子菌肺炎，最终放弃治疗出院。.

Topics: Acidosis, Lactic; Acidosis, Renal Tubular; Anemia; Antineoplastic Agents; Biopsy; Creatinine; Erythropoietin; Female; Humans; Lymphoma, Non-Hodgkin; Middle Aged; Nausea; Pneumonia, Pneumocystis; Prednisone; Renal Insufficiency; Sodium Bicarbonate; Treatment Refusal; Vomiting

Responsiveness to erythropoietin-stimulating agents (ESAs) is important for anemia management in chronic kidney disease (CKD). We assessed the effects of a continuous erythropoietin receptor activator (CERA) on renoprotection beyond anemia management and the correlation between the responsiveness to ESAs and oxidative stress markers in CKD.. This single-center, prospective, observational study was conducted over 24 months. We administered CERA to 35 non-dialysis patients with hemoglobin (Hb) < 11 g/dL and examined the results of the serum diacron-reactive oxygen metabolite (dROMs) test for oxidative stress markers and biological antioxidant potential (BAP) test for antioxidant markers. We then examined the renoprotective effects of CERA and the responsiveness to CERA.. Eighteen patients experienced renal events (doubling of serum creatinine levels, decreased estimated glomerular filtration rate to < 6.0 mL/min/1.73 m. Responsiveness to CERA during the first 3 months was an important indicator of CKD progression. Moreover, BAP test results determined responsiveness to CERA. This is the first report to show how antioxidant levels can be a potential marker of CERA's ability to control anemia in CKD patients.

Topics: Aged; Aged, 80 and over; Anemia; Antioxidants; Biomarkers; Creatinine; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Oxidative Stress; Polyethylene Glycols; Prognosis; Prospective Studies; Reactive Oxygen Species; Renal Insufficiency; Treatment Outcome

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Multiple Myeloma; Prognosis; Renal Insufficiency; Retrospective Studies; Survival Rate

Anaemia is a common complication of chronic kidney disease, for which there is presently no adequate treatment. The delivery of human erythropoietin (hEPO) cDNA to salivary glands reportedly increases red blood cell counts, haematocrit (HCT) and haemoglobin concentration, representing a potential new method of renal anaemia treatment. However, no studies have examined the effects of this method in an animal model of renal anaemia. Here we established a miniature pig animal model of renal anaemia through continuous feeding with adenine. In these animals, we delivered the AAV2hEPO gene to the parotid glands through Stensen's duct. As a control, we transferred AAVLacZ. Enzyme-linked immunosorbent assay was used to detect hEPO in serum and saliva. Red blood counts and serum biochemistry were used to evaluate how hEPO gene administration affected renal anaemia. Compared with the control group, we found increased hEPO concentrations in parotid saliva and serum, respectively, at 2 and 6 weeks after AAV2hEPO administration to the anaemic animals. HCT and haemoglobin were also increased after AAV2hEPO was delivered; most serum indicators of renal damage were not changed over the time span of the experiment, suggesting the adenine-induced kidney damage had not been completely reversed. However, blood urea nitrogen and B2 microglobulin levels showed small but significant improvement. Overall, our present findings suggest that adeno-associated virus 2 (AAV2)-mediated gene transduction of hEPO via the parotid gland is a promising potential alternative therapy for renal anaemia.

Topics: Adenoviridae; Anemia; Animals; Dependovirus; Disease Models, Animal; Erythropoietin; Gene Transfer Techniques; Genetic Vectors; Humans; Parotid Gland; Protein Transport; Renal Insufficiency; Saliva; Salivary Glands; Swine; Swine, Miniature; Transduction, Genetic

Remote ischemic preconditioning (RIPC) is an intriguing approach which exposes a remote organ/tissue to a non-lethal transient ischemia/reperfusion (I/R) in order to potentiate the resistance of the desired organ/tissue against the next unwanted I/R. It has been suggested that RIPC exerts its effect through neuronal and hormonal pathways. The underlying mechanisms of RIPC are obscure and should be elucidated. In this study, we induced RIPC in mice using 3 cycles of 5 min ischemia alternating with 5 min reperfusion of the left renal artery. Renal failure was induced in mice by intra-peritoneal (i.p.) injection of 200 mg/kg body weight of gentamicin twice per day for 4 consecutive days. Global hippocampal ischemia reperfusion (I/R) was performed by bilateral carotid artery occlusion for 20 min followed by reperfusion for 72 h. Moreover, the retention trial of passive avoidance test was determined 72 h after global ischemia. Histopathological changes of hippocampus neurons were observed using Nissl staining to detect neuronal loss. Finally, terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) was performed to assess the status of apoptotic cells in the hippocampus. The results of this study suggest that renal ischemic preconditioning is a good candidate for prevention of I/R-induced hippocampal injury. However, RRPC (remote renal preconditioning) failed to exert a neuroprotective effect in mice with renal failure (RF), indicating the probable role of a humoral factor which is released from kidneys in response to ischemia. In agreement with this hypothesis, treatment of mice with rhEPO (5000 IU/kg intraperitoneal) before induction of RRPC restored the neuroprotective effects of RRPC in RF mice. Accordingly, it is plausible to expect that erythropoietin is released from kidneys to act as a mediator for RRPC-induced neuroprotective effects. Renal ischemic preconditioning prevents I/R-induced hippocampal injury. In contrast, renal failure hampers protective effects of RRPC, while exogenous administration of erythropoietin (EPO) significantly prevents the inhibiting effects of renal failure.

Topics: Animals; Avoidance Learning; Erythropoietin; Hippocampus; Ischemic Preconditioning; Kidney; Mice; Renal Insufficiency; Reperfusion Injury

Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear.. We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06-1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P < 0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05-2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level.. A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

Topics: Acute Disease; Aged; Aged, 80 and over; Anemia; Cause of Death; Cohort Studies; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Heart Failure; Hemoglobins; Humans; Lactic Acid; Male; Middle Aged; Mortality; Multivariate Analysis; Oximetry; Plasma Volume; Prognosis; Proportional Hazards Models; Prospective Studies; Registries; Renal Insufficiency

Anemia is defined as a reduction in the hemoglobin concentration of blood, which consequently reduces the oxygen-carrying capacity of red blood cells such that they are unable to meet the body's physiological needs. Several reports have indicated that anemia mostly occurs in patients with diabetes with renal insufficiency while limited studies have reported the incidence of anemia in people with diabetes prior to evidence of renal impairment. Other studies have also identified anemia as a risk factor for the need for renal replacement therapy in diabetes. Understanding the pathogenesis of anemia associated with diabetes may lead to the development of interventions to optimize outcomes in these patients. The aim of this study was therefore to determine the prevalence of anemia among patients with type 2 diabetes.. A total of 100 (50 with type 2 diabetes and 50 controls) participants were recruited for our study. Participants' blood samples were analyzed for fasting blood glucose, full blood count and renal function tests among others. The prevalence of anemia was then determined statistically.. A high incidence of anemia was observed in the cases. Of the patients with diabetes, 84.8% had a hemoglobin concentration that was significantly less (males 11.16±1.83 and females 10.41±1.49) than the controls (males 14.25±1.78 and females 12.53±1.14). Renal insufficiency determined by serum creatinine level of >1.5 mg/dL, estimated glomerular filtration rate <60 ml/minute/1.73 m2, and erythropoietin levels was also observed to be high in the cases (54.0%; with mean creatinine concentration of 3.43±1.73 and erythropoietin 6.35±1.28 mIU/mL). A significantly increased fasting blood glucose, urea, sodium, potassium, and calcium ions were observed in the cases (7.99±1.30, 5.19±1.99, 140.90±6.98, 4.86±0.53 and 1.47±0.31 respectively) as compared to the controls (4.66±0.54, 3.56±2.11, 135.51±6.84, 4.40±0.58 and 1.28±0.26 respectively). Finally, a significant association between hemoglobin concentration and fasting blood glucose was also observed in the cases.. The findings suggest that a high incidence of anemia is likely to occur in patients with poorly controlled diabetes and in patients with diabetes and renal insufficiency.

Topics: Adult; Aged; Anemia; Blood Glucose; Calcium; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Erythropoietin; Female; Ghana; Hemoglobins; Humans; Male; Middle Aged; Potassium; Prevalence; Renal Insufficiency; Sodium; Urea

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

Mitomycin C (MMC) is one of the most effective chemotherapeutic drugs. However, the dose of MMC is greatly limited by its toxicity in normal tissues. Recombinant human erythropoietin (rhEPO), an erythropoietic hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against MMC-induced heart, liver, and renal dysfunction. Adult male Wistar rats were divided into six groups (with six animals each), namely control, rhEPO alone group, MMC alone group, and rhEPO + MMC group (pre-, co-, and posttreatment conditions). The results showed that MMC induced a marked cardiac, renal, and liver failure characterized by a significant decrease in body weight, organs weight, and organs ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, and conjugated and total bilirubin levels in serum. Histological examination showed that MMC caused liver alterations. rhEPO treatment restored body weight, organs weight, and organs ratio as well as serum biochemical parameters and histological damage caused by MMC exposure.

Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Erythropoietin; Heart Failure; Kidney Function Tests; Liver Function Tests; Male; Mitomycin; Organ Size; Rats, Wistar; Recombinant Proteins; Renal Insufficiency

Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.. Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.. Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.. Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Darbepoetin alfa; Erythropoietin; Inflammation; Mice; Mice, Knockout; Oxidative Stress; Renal Insufficiency

Inflammation contributes to hemopoiesis by lowering responses to epoetin (EPO) and to an increase in the mortality of patients on hemodialysis. However, nutritional status might alter associations among inflammation, EPO responsiveness, and the risk of mortality. We assessed the effect of inflammation on mortality according to nutritional status among EPO responses in a cohort of prevalent hemodialysis patients.. The observational cohort study analyzed data from the Japanese Dialysis Registry (2005-2006; n = 36,956; mean follow-up 11.5 months). Patients were categorized into tertiles of the EPO responsiveness index (ERI; the weekly weight-adjusted EPO dose [IU/kg/week] divided by hemoglobin [g/dL]) and an EPO-free group. Body mass index (BMI) and C-reactive protein (CRP) levels were measured.. Bimodal peaks indicated associations between CRP and BMI in each group. Hazard ratio (HR) curves of CRP for mortality according to BMI in the upper ERI tertile, particularly among those with diabetes mellitus (DM), were reverse J-shaped. However, HR curves in the other groups were increased below a threshold BMI of 21 kg/m(2). These associations were confirmed in propensity score-matched populations.. Risk of CRP for death is apparently changed by BMI in hemodialysis patients with a lower EPO response, especially in those with DM.

Topics: Aged; Body Mass Index; C-Reactive Protein; Cohort Studies; Diabetes Mellitus; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Nutritional Status; Renal Dialysis; Renal Insufficiency

The haematopoietic activity of erythropoietin (EPO) is mediated by the classic EPO receptor (EpoR) homodimer, whereas tissue-protective effects are mediated by a heterocomplex between EpoR and the β-common receptor (βcR). Here, we investigated the effects of a novel, selective ligand of this heterocomplex - pyroglutamate helix B surface peptide (pHBSP) - in mice fed a diet enriched in sugars and saturated fats.. Male C57BL/6J mice were fed a high-fat high-sucrose diet (HFHS) for 22 weeks. pHBSP (30 μg·kg(-1) s.c.) was administered for the last 11 weeks. Biochemical assays, histopathological and immunohistochemical examinations and Western blotting were performed on serum and target organs (liver, kidney and skeletal muscle).. Mice fed with HFHS diet exhibited insulin resistance, hyperlipidaemia, hepatic lipid accumulation and kidney dysfunction. In gastrocnemius muscle, HFHS impaired the insulin signalling pathway and reduced membrane translocation of glucose transporter type 4 and glycogen content. Treatment with pHBSP ameliorated renal function, reduced hepatic lipid deposition, and normalized serum glucose and lipid profiles. These effects were associated with an improvement in insulin sensitivity and glucose uptake in skeletal muscle. Diet-induced overproduction of the myokines IL-6 and fibroblast growth factor-21 were attenuated by pHBSP and, most importantly, pHBSP markedly enhanced mitochondrial biogenesis in skeletal muscle.. Chronic treatment of mice with an EPO derivative, devoid of haematopoietic effects, improved metabolic abnormalities induced by a high-fat high-sucrose diet, by affecting several levels of the insulin signalling and inflammatory cascades within skeletal muscle, while enhancing mitochondrial biogenesis.

Topics: Animals; Blood Glucose; Dietary Fats; Dietary Sucrose; Erythropoietin; Fatty Liver; Hyperlipidemias; Insulin Resistance; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Oligopeptides; Renal Insufficiency

Erythropoietin (EPO) improves measures of quality of life and reduces transfusions. Clinical trials have reported higher mortality associated with higher hemoglobin targets in varied clinical settings, making difficult the selection of erythropoiesis stimulation strategies in end-stage kidney disease. Observational studies distinguishing an effect of EPO from underlying conditions are challenging, but promise insights relevant to real-world settings.. Using data from the United States Renal Data System, we performed a retrospective cohort study of hemodialysis patients treated between 2000 and 2004. 409 364 Medicare insured patients receiving hemodialysis therapy as of January 2000 or who began dialysis after January 2000 and survived >6 months were studied. We examined the association of EPO dose in any given month with death over subsequent follow-up.. Within each hematocrit group (<30%, 30%–< 33%, 33%–< 36%, 36%–< 39% and >39%), the hazard ratios comparing the 80th percentile to the median EPO dose were 0.88 (95% CI: [0.87–0.90]), 0.94 ([0.93–0.94]), 0.98 ([0.98–0.99]), 1.06 ([1.05–1.06]) and 1.08 ([1.07–1.09]), respectively. Within the highest hematocrit group, the association of a high EPO dose with elevated mortality was attenuated over time. Among patients with malignancy or indications of EPO resistance, the association of higher EPO dose with lower mortality was attenuated when hematocrit was low, while its association with higher mortality was stronger when hematocrit was high.. These analyses demonstrate a complex relationship between EPO dosing and mortality, suggesting a possible beneficial effect among severely anemic hemodialysis patients, but possible harm when administered to individuals with higher hematocrit levels.

Topics: Dose-Response Relationship, Drug; Erythropoietin; Female; Hematocrit; Humans; Male; Medical Record Linkage; Mortality; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency; United States

Hypoxia-inducible factor (HIF) activity during the course of chronic kidney disease (CKD) development is poorly defined, and the effect of HIF activation on CKD is still controversial. The purpose of the present study was to characterize HIF expression during the course of CKD development, and to investigate the effect of HIF activation on CKD by using prolyl hydroxylase (PHD) inhibitor L-mimosine.. Rats with remnant kidneys (RK) were killed at week 1, 2, 4, 6, 8, 12 after subtotal nephrectomy. An additional group of RK rats was treated with L-mimosine to study the effect of HIF-α activation.. Tubulointerstitial hypoxia in the remnant kidney began at week 1 and continued, albeit attenuated, until week 12, the last time point examined. The nuclear expression of HIF-1α and HIF-2α, as well as typical HIF target genes VEGF (vascular endothelial growth factor), HO-1 (heme oxygenase-1), GLUT-1 (glucose transporter-1) and EPO (erythropoietin), were all upregulated in the early stage of RK when renal function was stable, and returned to the basal level later, accompanied by impaired renal function and interstitial fibrosis. L-mimosine administered from week 5 to week 12 led to accumulation of HIF-1α and HIF-2α proteins, increased expression of VEGF, HO-1 and GLUT-1, and improved renal function. Furthermore, fibrosis markers α-smooth muscle actin (α-SMA) and Collagen III, as well as peritubular capillary rarefaction index, were all significantly decreased after L-mimosine treatment.. There was a transient HIF-α activation in the remnant kidney of rats at the early stage following subtotal nephrectomy. L-mimosine administered in later stages re-activated HIF-α and reduced tubulointerstitial fibrosis.

Topics: Albuminuria; Animals; Blood Pressure; Disease Models, Animal; Erythropoietin; Glucose Transporter Type 1; Heme Oxygenase-1; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Kidney Function Tests; Mimosine; Nephrectomy; Procollagen-Proline Dioxygenase; Rats; Renal Insufficiency; Up-Regulation; Vascular Endothelial Growth Factor A

Cisplatin (Cisp) is an active cytotoxic agent that was found efficient in the treatment of various types of solid tumors. Its nephrotoxic effect has been very well documented in clinical oncology. Erythropoietin (EPO), a renal cytokine-regulating hematopoiesis, has recently been shown to exert important cytoprotective effects in many experimental injuries. The aim of this study was to explore whether EPO would protect against Cisp-induced apoptosis in rat kidney. Adult Wistar rats were treated with saline solution as the control group, Cisp alone, EPO alone, or EPO with Cisp in different treatments: 1) EPO and Cisp simultaneously administrated to animals as a cotreatment; 2) EPO administered 24 hours before Cisp as a pretreatment; and 3) EPO administered 5 days after Cisp injection as a post-treatment. Our results have shown that Cisp induced renal failure, characterized with a significant increase in serum creatinine and blood urea nitrogen (BUN) concentrations. Cisp promoted kidney DNA fragmentation and apoptotic cell death. Apoptosis was revealed by an enhancement of proapoptotic protein (e.g., p53 and Bax) levels, decrease in antiapoptotic proteins (e.g., Bcl2 and Hsp27), and increase in caspase-3 activity. Treatments with EPO restored creatinine and BUN levels and inhibited Cisp-induced DNA damage in the kidney. Apoptosis was also reduced by the upregulation of antiapoptotic protein expressions, downregulation of proapoptotic protein levels, and reduction of caspase-3 activity.

Topics: Animals; Antimutagenic Agents; Antineoplastic Agents; Apoptosis; Blood Urea Nitrogen; Cisplatin; Creatinine; DNA Damage; DNA Fragmentation; Down-Regulation; Erythropoietin; Kidney; Male; Mutagens; Rats; Rats, Wistar; Renal Insufficiency; Up-Regulation

This study assessed the added effect of 6 months of erythropoietin (EPO) administration in patients suffering from diabetic neuropathy with mild to moderate chronic kidney disease (CKD) managed with gabapentin. Twenty diabetic patients with mild to moderate CKD were included; 12 in gabapentin and 8 in EPO+gabapentin group. The subjects underwent nerve conduction studies (NCS) at the initiation of the investigation and after 6-month treatment. NCS were made in deep and superficial peroneal, tibial, and sural nerves. After 6 months, in both the groups, proximal motor latency (PML) nonsignificantly improved in deep peroneal and tibial nerves; conversely, dorsal motor latency (DML) got slightly impaired in these two nerves. A nonsignificant disruption and improvement was observed in deep peroneal and tibial motor nerve conduction velocity (MNCV), respectively, in gabapentin group. Although the F-wave of tibial and deep peroneal nerves remained stable in gabapentin group, a nonsignificant improvement was observed in EPO+gabapentin group. H-reflex of tibial nerve and all the evaluated parameters of sural and superficial peroneal nerves remained constant in all patients. Thus, it can be concluded that 6-month administration of EPO+gabapentin, or gabapentin alone in mild to moderate CKD patients with diabetic neuropathy could not improve nerve performance.

Topics: Aged; Aged, 80 and over; Amines; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Drug Therapy, Combination; Erythropoietin; Excitatory Amino Acid Antagonists; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neural Conduction; Neurologic Examination; Peripheral Nervous System Diseases; Peroneal Nerve; Recombinant Proteins; Renal Insufficiency; Sural Nerve; Surveys and Questionnaires; Tibial Nerve

Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Base Sequence; Cells, Cultured; Erythropoiesis; Erythropoietin; Feasibility Studies; Female; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Procollagen-Proline Dioxygenase; Renal Insufficiency; RNA Interference; RNA, Small Interfering

Activity of plasma proteolytic systems (fibrin formation, fibrinolysis, and anticoagulant system) and the possibility for correction of changes in these systems with erythropoietin were studied in experiments on outbred albino rats with experimental renal failure. Renal failure was induced by a single subcutaneous injection of mercury chloride (II). The parameters were estimated on day 5 postinjection. Erythropoietin in a single dose of 5000 U/kg was administered on day 4. Renal failure was accompanied by activation of fibrin formation (with factors of the common and intrinsic pathways of blood coagulation), increase in antithrombin activity, and inhibition of the fibrinolytic system. Treatment with erythropoietin led to partial recovery of fibrin formation and fibrinolysis. Under analytical in vitro conditions, 30-min incubation of whole blood from healthy donors with erythropoietin in doses of 1.9-30.0 U/liter was followed by a dose-dependent inhibition of the fibrin formation system and activation of fibrinolysis.

Topics: Animals; Blood Coagulation; Erythropoietin; Fibrin; Fibrinolysis; Humans; Male; Random Allocation; Rats; Renal Insufficiency

We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

Topics: Anemia; Bayes Theorem; Biostatistics; Dose-Response Relationship, Drug; Erythropoietin; Hemoglobins; Humans; Likelihood Functions; Models, Statistical; Normal Distribution; Regression Analysis; Renal Insufficiency; Statistics, Nonparametric

For decades, autologous ex vivo gene therapy has been postulated as a potential alternative to parenteral administration of recombinant proteins. However, achieving effective cellular engraftment of previously retrieved patient cells is challenging. Recently, our ability to engineer vasculature in vivo has allowed for the introduction of instructions into tissues by genetically modifying the vascular cells that build these blood vessels. In the present study, we genetically engineered human blood-derived endothelial colony-forming cells (ECFCs) to express erythropoietin (EPO) under the control of a tetracycline-regulated system, and generated subcutaneous vascular networks capable of systemic EPO release in immunodeficient mice. These ECFC-lined vascular networks formed functional anastomoses with the mouse vasculature, allowing direct delivery of recombinant human EPO into the bloodstream. After activation of EPO expression, erythropoiesis was induced in both normal and anemic mice, a process that was completely reversible. This approach could relieve patients from frequent EPO injections, reducing the medical costs associated with the management of anemia. We propose this ECFC-based gene-delivery strategy as a viable alternative technology when routine administration of recombinant proteins is needed.

Topics: Anemia; Animals; Blood Vessels; Cells, Cultured; Disease Models, Animal; Erythropoiesis; Erythropoietin; Feasibility Studies; Gene Expression Regulation; Genetic Engineering; Genetic Therapy; Humans; Mesenchymal Stem Cell Transplantation; Mice; Mice, Nude; Radiation Injuries; Renal Insufficiency; Subcutaneous Tissue; Transfection; Transplantation, Autologous; Transplantation, Heterologous

Topics: Anemia; Erythropoietin; Europe; Heart Failure; Humans; Iron Compounds; Renal Insufficiency

Topics: Anemia; Animals; Congresses as Topic; Erythropoietin; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency

This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the annual meeting of the European Society of Cardiology held in Stockholm in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. The SHIFT study supports the use of ivabradine in patients with HF due to left ventricular systolic dysfunction and resting sinus rhythm rate ≥70 b.p.m. despite treatment with beta-blockers or where beta-blockers are contra-indicated. Results from PEARL-HF suggest that the potassium binding polymer RLY5016 may be useful for both prevention and treatment of hyperkalaemia in HF patients with or without concomitant chronic kidney disease. The STAR-heart study provides encouraging observational data about the potential for intracoronary stem cell transplantation in patients with HF. Results from HEBE-III showed no effect of erythropoietin on ejection fraction measured 6 weeks post-MI; although there were fewer cardiovascular events in patients assigned to erythropoietin, the study was too small to provide conclusive evidence of effect.

Topics: Adrenergic beta-Antagonists; Benzazepines; Clinical Trials as Topic; Comorbidity; Cyclic Nucleotide-Gated Cation Channels; Drug Therapy, Combination; Erythropoietin; Heart Failure; Hematinics; Humans; Hyperkalemia; Ivabradine; Myocardial Infarction; Polymers; Renal Insufficiency; Stem Cell Transplantation

Topics: Anemia; Animals; Asialoglycoproteins; Erythropoietin; Heart Failure; Humans; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency; Signal Transduction

We examined the effect of asialoerythropoietin (asialoEPO), a nonerythrogenic derivative of erythropoietin (EPO), on renal dysfunction-associated heart failure.. Although EPO is known to exert beneficial effects on cardiac function, the clinical benefits in patients with chronic kidney disease are controversial. It remains to be addressed whether previously reported outcomes were the result of relief of the anemia, adverse effects of EPO, or direct cardiovascular effects.. Mice underwent 5/6 nephrectomy to cause renal dysfunction. Eight weeks later, when renal dysfunction was established, anemia and cardiac dysfunction and remodeling were apparent. Mice were then assigned to receive saline (control), recombinant human erythropoietin (rhEPO) at 5,000 IU (714 pmol)/kg, or asialoEPO at 714 pmol/kg, twice/week for 4 weeks.. Although only rhEPO relieved the nephrectomy-induced anemia, both rhEPO and asialoEPO significantly and similarly mitigated left ventricular dilation and dysfunction. The hearts of rhEPO- or asialoEPO-treated mice showed less hypertrophy, reflecting decreases in cardiomyocyte hypertrophy and degenerative subcellular changes, as well as significant attenuation of fibrosis, leukocyte infiltration, and oxidative deoxyribonucleic acid damage. These phenotypes were accompanied by restored expression of GATA-4, sarcomeric proteins, and vascular endothelial growth factor and decreased inflammatory cytokines and lipid peroxidation. Finally, myocardial activation was observed of extracellular signal-regulated protein kinase and signal transducer and activator of transcription pathways in the treated mice.. EPO receptor signaling exerts direct cardioprotection in an animal model of renal dysfunction-associated heart failure, probably by mitigating degenerative, pro-fibrosis, inflammatory, and oxidative processes but not through relief of anemia.

Topics: Anemia; Animals; Asialoglycoproteins; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Heart Failure; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency; Signal Transduction

In July 2004, an anemia outbreak was identified in our hemodialysis (HD) unit. The dialysate chloramine levels had risen from <0.1 mg/mL in May to 0.27 mg/mL in August 2004. Other parameters of water quality were within accepted standards. Hematocrit (Ht) and hemoglobin (Hb) returned to basal values after one month without changing recombinant human erythropoetin (rHuEpo) doses and with exchange of activated charcoal column. Chloramines (chlorine and ammonia) are used routinely to disinfect and sterilize potable water. High blood levels of chloramines are associated with hemolysis and rarely methemoglobinemia. Uremic patients have a decreased ability to withstand oxidative stress. It is postulated that their antioxidant capacity is reduced, yet the mechanism remains unclear. Patients on maintenance hemodialysis are vulnerable to chloramine toxicity if chloramines are inadequately removed from water.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Chloramines; Cohort Studies; Dialysis Solutions; Disease Outbreaks; Erythropoietin; Female; Hemodialysis Units, Hospital; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Risk Factors; Water Purification

Topics: Animals; Endothelium, Vascular; Erythropoietin; Heme Oxygenase-1; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

We previously demonstrated that erythropoietin (EPO)-secreting mesenchymal stromal cells (MSC) can be used for the long-term correction of renal failure-induced anemia. The present study provides evidence that coimplantation of insulin-like growth factor I (IGF-I)-overexpressing MSC (MSC-IGF) improves MSC-based gene therapy of anemia by providing paracrine support to EPO-secreting MSC (MSC-EPO) within a subcutaneous implant. IGF-I receptor RNA expression in murine MSC was demonstrated by RT-PCR. Functional protein expression was confirmed by immunoblots and MSC responsiveness to IGF-I stimulation in vitro. IGF-I was also shown to improve MSC survival following staurosporin-induced apoptosis in vitro. A cohort of C57Bl/6 mice was rendered anemic by right kidney electrocoagulation and left nephrectomy. MSC-EPO were subsequently admixed in a bovine collagen matrix and implanted, in combination with MSC-IGF or MSC null, by subcutaneous injection in renal failure mice. In mice receiving MSC-EPO coimplanted with MSC-IGF, hematocrit elevation was greater and enhanced compared with control mice; heart function was also improved. MSC-IGF coimplantation, therefore, represents a promising new strategy for enhancing MSC survival within implanted matrices and for improving cell-based gene therapy of renal anemia.

Topics: Anemia; Animals; Apoptosis; Cells, Cultured; Disease Models, Animal; Erythropoietin; Female; Genetic Engineering; Genetic Therapy; Hematocrit; Insulin-Like Growth Factor I; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Receptor, IGF Type 1; Renal Insufficiency; RNA, Messenger

Topics: Acetylcysteine; Aged; Aortic Valve; Aortic Valve Insufficiency; Aspartate Aminotransferases; Bilirubin; Cardiac Catheterization; Drug Administration Schedule; Erythropoietin; Ferrous Compounds; Folic Acid; Glucose; Heart Valve Prosthesis; Hematinics; Hemoglobinuria; Hemolysis; Humans; Infusions, Intravenous; L-Lactate Dehydrogenase; Male; Mitral Valve; Mitral Valve Insufficiency; Renal Insufficiency; Treatment Outcome; Ultrasonography

Anaemia is prevalent in chronic kidney disease (CKD) and induces significant changes in heart and kidney. In this study, we evaluated the relationship between iron metabolism, hepcidin and inflammation focusing on left ventricular (LV) function, in a remnant kidney rat model.. Rats with 5/6 subtotal nephrectomy (STNx) and sham operation. Haemoglobin (Hb), serum iron (SI), fractional shortening (FS%) by echocardiograms were evaluated. Six months after STNx, the heart and kidney were processed by immunohistochemistry with antibodies against hypoxia-inducible factors (HIF)-1alpha, erythropoietin (EPO), pro-hepcidin, caspase-3, tumour necrosis factor (TNF)-alpha and interleukin (IL)-6.. Hb (g/dL) STNx: 10.8 +/- 0.8, sham: 14.7 +/- 0.6 (P < 0.01); SI (microg/dL) STNx: 154.5 +/- 24.5, sham: 287.5 +/- 32.1 (P < 0.01); heart weight (g) STNx: 2.21 +/- 0.15, sham: 1.12 +/- 0.12 (P < 0.01); FS% STNx: 28.4 +/- 2.5, sham: 45.1 +/- 4.1 (P < 0.01). There was a correlation between Hb and FS% (r = 0.95; P < 0.01) and between SI and FS% (r = 0.86; P < 0.01) in the STNx group. Tissue ferritin was reduced in heart and in kidney in the STNx group (P < 0.01). HIF-1alpha was expressed in cardiomyocytes (positive cells/area) STNx: 32 +/- 5, sham: 4 +/- 1; and tubular cells in STNx group: 70 +/- 16, sham: 10 +/- 3, P < 0.01. Hepcidin (% staining/area) in heart STNx: 6.6 +/- 0.8, sham: 0.8 +/- 0.1; in kidney STNx: 9.7 +/- 2.6, sham: 3.7 +/- 0.9, P < 0.01. EPO (% staining/area) in heart STNx: 2.6 +/- 0.4, sham: 0.8 +/- 0.2; in kidney STNx: 10.2 +/- 1.4, sham: 1.2 +/- 0.6; P < 0.01. In STNx group positive caspase-3, TNF-alpha and IL-6 were detected in heart and renal cells.. Low LV performance is associated with iron deficiency anaemia in rats with CKD. Furthermore, overproduction of HIF-1alpha and the activation of caspase-3 seem to be associated with iron deficiency and with inflammatory markers. Hepcidin seems to plays a key role in this mechanism.

Topics: Anemia, Iron-Deficiency; Animals; Antimicrobial Cationic Peptides; Caspase 3; Erythropoietin; Ferritins; Hepcidins; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Interleukin-6; Kidney; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Tumor Necrosis Factor-alpha; Ventricular Function, Left

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Insufficiency; Time Factors

Although multifactorial anemia is common following orthotopic liver transplantation (OLT), the late introduction of sirolimus (SRL) has been associated with high rates of anemia, whose pathogenic mechanisms have not been fully studied. Herein we have described a case of severe anemia in an HIV+ OLT patient who was switched from calcineurin inhibitors (CNI) to SRL due to severe nephrotoxicity. After 22 weeks of SRL, hemoglobin levels dropped 4 g/dL to a nadir of 6.5 g/dL. After discarding other causes for anemia, we concluded that it displayed the features of anemia of a chronic inflammatory state (ACIS): decreased mean corpuscular volume (MCV), low serum iron despite high ferritinemia, and elevated fibrinogen and C-reactive protein (CRP) levels. SRL trough levels were never above the therapeutic range. After blood transfusions and erythropoietin (EPO) use, SRL was maintained within the lower range of therapeutic levels, with significant improvement in renal function. As described among kidney transplant recipients, SRL-related anemia in this HIV+ patient with CNI nephrotoxicity after OLT showed features of ACIS. Blood transfusions and EPO use allowed SRL maintenance.

Topics: Adaptor Proteins, Signal Transducing; Anemia; Blood Transfusion; C-Reactive Protein; Calcineurin; Erythropoietin; HIV Seropositivity; Humans; Immunosuppressive Agents; Inflammation; Iron; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Sirolimus; Transferrin

Anaemia is a common complication of renal failure. It can be treated with erythropoietin (EPO) administration, red blood cell transfusion (RBCT), or a combination of both. EPO has been registered for the treatment of renal anaemia in Sweden since the beginning of the 1990s, and is the primary treatment regimen for anaemia related to renal failure. The objective of this study was to carry out a cost-effectiveness analysis from a provider perspective of a treatment strategy comprising EPO and complementary RBCT compared to the traditional treatment of RBCT alone for patients with anaemia associated with renal failure in Sweden.. Incremental costs and quality-adjusted life-years (QALYs) associated with EPO (epoietin-alpha) treatment compared to the traditional therapy of RBCT were estimated. The QALY gains were estimated using a modified version of a Markov model, which is used by the UK National Institute of Clinical Excellence in their evaluations of EPO treatment in the UK. Swedish treatment practice (i.e. EPO doses and iron supplementation), patient characteristics and unit costs were used throughout the study.. The estimated cost per QALY gained from administration of EPO to renal patients falls within the range acceptable in Sweden for both haemodialysis and peritoneal dialysis patients.. EPO administration to renal patients is much more costly in Sweden than in the UK, primarily due to the higher dosage of EPO and iron supplementation used in Sweden. However, Swedish patients reach higher haemoglobin levels, and thereby achieve higher QALY gains, compared to patients in the UK.

Topics: Anemia; Cost-Benefit Analysis; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Health Care Costs; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Sweden; Treatment Outcome

HFE protein controls iron absorption and cycling, and HFE mutations influence iron status. The aim was to evaluate the effect of the HFE genotype on the need for iron and erythropoietin in Italian hemodialysis patients.. Ninety-six prevalent patients were evaluated at the time of enrolment and prospectively followed for 3 years. Patients were given r-HuEPO and Fe3+-gluconate according to guidelines. The HFE genotype was determined by restriction analysis.. Three patients (3%) carried the C282Y mutation, 4 (4%) were homozygous and 18 (19%) heterozygous for the H63D mutation, and 71 (74%) were negative for both. At enrolment, subjects positive for HFE mutations had higher iron stores (ferritin 617 +/- 663 vs. 423 +/- 386 ng/ml, p = 0.05), were receiving less iron (82.5 +/- 66 vs. 110 +/- 154 mg/month, p = 0.05) and a lower r-HuEPO dosage (98 +/- 83 vs. 142 +/- 138 U/kg/week, p = 0.03). Consistently during the study period, patients positive for HFE mutations received a lower amount of r-HuEPO (94.5 +/- 63 vs. 186 +/- 344 U/kg/week, p = 0.01) and iron (97 +/- 63 vs. 121 +/- 68 mg/month, p = 0.07). Upon Cox regression analysis, after adjustment for confounding variables, the presence of HFE mutations was associated with a reduced risk of death (HR 0.6, 95% CI 0.34-1.03, p = 0.06).. HFE mutations reduce the amount of r-HuEPO and iron necessary to support erythropoiesis in hemodialysis.

Topics: Aged; Erythropoiesis; Erythropoietin; Female; Genotype; Hemochromatosis Protein; Histocompatibility Antigens Class I; Humans; Iron; Italy; Male; Membrane Proteins; Middle Aged; Mutation; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

In order to evaluate medical management in patients with renal failure before dialysis, we conducted a case-control study to analyze the health benefits in 914 moderate renal failure patients with Cockcroft clearance between 30 and 60 ml/min. Health benefits reimbursed by the Social Security in this population were compared with those in 1828 controls randomly chosen in the Social Security files but matched by age and gender. Mean age of the participants was 73+/-11 year-old, 67% were women, Cockcroft clearance was 48+/-8 ml/min. Number of hospitalizations and hospitalization durations were not different between the two populations. Conversely, cases had more specialized outpatients' clinics in cardiology but not in nephrology or urology. Cases had more biological tests and radiological exams and had taken more medicines. For biology, cases had more often renal function tests and markers of renal dysfunction tests than controls. Cases had taken more medicines than controls for erythropoietin, diuretics, renin-angiotensin blockers, hypoglycemic drugs, and anticoagulants. Patients with mild renal failure had higher health benefits than controls for outpatients' clinics in cardiology, for biological tests, for radiological exams, and for some medicines.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Creatinine; Erythropoietin; France; Hospitalization; Humans; Insurance Benefits; Middle Aged; Renal Insufficiency

Recombinant human erythropoietin (rHuEpo) is a definitive treatment for anaemia in chronic kidney disease (CKD). During long-term rHuEpo treatment most patients develop and show persistent iron deficiency in spite of oral iron supplementation. Abnormalities of iron absorption and transport in the duodenum may contribute to this deficiency.. To investigate changes in iron absorption and transport in CKD and iron deficiency against the background of rHuEpo treatment, we used severely anaemic rats with adenine-induced renal failure (adenine rats) and sham-treated control rats given only the vehicle. After 4 weeks on adenine or the vehicle, the rats were divided into four groups according to whether or not they received rHuEpo for the next 4 weeks: rHuEpo(-)-adenine, rHuEpo(-)-control, rHuEpo(+)-adenine and rHuEpo(+)-control. We evaluated the effects of rHuEpo treatment on iron balance, duodenal mRNA expression of molecules related to iron absorption and transport and hepatic mRNA expression of hepcidin.. Treatment with rHuEpo improved anaemia and induced iron deficiency only in the adenine rats, in whom the expression of mRNAs for ferroportin 1 and hephaestin 1 increased and for divalent metal transporter 1 (DMT1) was unchanged. In contrast, control rats treated with rHuEpo showed no changes. Hepcidin mRNA expression was greater in adenine rats than in control rats.. In the adenine rats, rHuEpo treatment improved renal anaemia and induced persistent iron deficiency. An alteration of mRNA expression of molecules related to iron metabolism in renal insufficiency may be one of the reasons for this iron deficiency.

Topics: Adenine; Analysis of Variance; Anemia, Iron-Deficiency; Animals; Antimicrobial Cationic Peptides; Disease Models, Animal; Erythrocytes; Erythropoietin; Hepcidins; Humans; Iron; Kidney Failure, Chronic; Kidney Function Tests; Male; Polymerase Chain Reaction; Probability; Random Allocation; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency; RNA, Messenger

Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning are well established in the heart, but their mechanisms still remain to be elucidated. Hence, the present study was designed to investigate the possible involvement of erythropoietin in remote renal preconditioning (RRPC)-induced cardioprotection in rats. RRPC was performed by 4 episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Gentamicin (100 mg/kg intraperitoneal) was administered for 6 days for induction of renal failure. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min ischemia followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. RRPC prevented I/R-induced myocardial injury and produced cardioprotective effects. However, cardioprotective effects of RRPC were not observed in renal failure rats, indicating the protective role of humoral factor was released from functional kidneys. In renal failure rats, exogenous administration of rhEPO (5,000 IU/kg intraperitoneal) with RRPC restored the cardioprotective effects of later. These results implicate that RRPC-induced cardioprotective effects may be mediated through release of erythropoietin from kidney.

Topics: Analysis of Variance; Animals; Coronary Circulation; Creatine Kinase; Erythropoietin; Gentamicins; In Vitro Techniques; Ischemic Preconditioning; Kidney; L-Lactate Dehydrogenase; Male; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Recombinant Proteins; Renal Insufficiency

Numerous studies using erythropoietin (EPO) gene delivery vectors, either viral or nonviral, have shown uncontrolled EPO expression leading to transient or sustained erythrocytosis and, more recently, severe autoimmune anemia. Therefore, there is a need to develop other EPO gene delivery systems that allow sustained and adjustable expression of EPO. We have examined a new approach of delivering plasmid encoding mouse EPO cDNA into mouse skeletal muscle, using an amphiphilic block copolymer. Repeated injections of low doses of block copolymer-EPOcDNA formulations increased hematocrit in a dose-dependent manner for more than 9 months, without any initial overshoot. Low doses of block copolymer-EPOcDNA formulations prevented autoimmune anemia in immunocompetent Swiss mice and prevented or reversed chronic anemia in an acquired mouse model of renal failure. We conclude that repeated injections of low doses of block copolymer-DNA formulations that do not induce (1) inflammation at the injection site, (2) overexpression of EPO, or (3) the production of anti-EPO neutralizing auto-antibodies hold promise for in vivo expression of therapeutic proteins, in particular for systemic delivery.

Topics: Anemia; Animals; Creatinine; Disease Models, Animal; Erythropoietin; Female; Genetic Therapy; Inflammation; Injections, Intramuscular; Kidney; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Plasmids; Polyethylene Glycols; Renal Insufficiency; Reticulocyte Count; Urea

The aim of the present study was to analyze the relations between the serum anti-erythropoietin antibody (AEAb) levels and the antibodies' neutralizing activity in 20 patients with renal anemia and rhEPO-induced antibodies. AEAb levels were determined by the enzyme-linked immunosorbent assay (ELISA, double antigen-bridging) and by radioimmunoprecipitation assay (RIPA). The bone marrow neutralization test was used to determine the neutralizing activity of the antibodies. RIPA and ELISA data resulted in closely correlated measurements. The relations between AEAb levels and the neutralizing activity of the antibodies are variable as shown by follow-up and cross-sectional evaluations of the data. Serum samples with a high antibody level (>1000 ng/ml) are associated with 100% neutralizing activity, whereas serum samples with lower AEAb levels show partial neutralizing activities or have no effect. Determining the neutralizing activity might be helpful when it comes to deciding of whether or not rhEPO therapy should be continued, specifically in patients who have low antibody levels. The apparent affinity of the AEAb as defined by inhibition of the binding of rhEPO (IC(50)) did not change in the course of the disease, nor did it correlate to the AEAb levels or the neutralizing activities.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antibodies; Antibody Affinity; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Neutralization Tests; Radioimmunoprecipitation Assay; Recombinant Proteins; Renal Insufficiency

The prevalence of anti-erythropoietin antibodies in renal patients without clinical evidence of pure red cell aplasia (PRCA) who respond poorly to epoetin is unknown. This study tested for anti-erythropoietin antibodies in hemodialysis patients who were either hypo- or normoresponsive to epoetin treatment.. Epoetin hyporesponsiveness (hemoglobin < or =10.5 g/dl and epoetin > or =9,000 IU/week) and normoresponsiveness (hemoglobin >10.5 g/dl and epoetin <7,000 IU/week) were arbitrarily defined. Prevalence of anti-erythropoietin antibodies in hemodialysis patients without symptoms of PRCA was determined by screening sera of 536 patients from 35 German KfH dialysis units, using enzyme-linked immunosorbent assay (ELISA). Positive results were verified by radioimmunoprecipitation assay (RIP) and neutralizing activity was determined by bioassay.. Anti-erythropoietin antibodies were detected in 3 hyporesponsive and 3 normoresponsive patients using ELISA. One patient per group was verified as borderline by RIP testing; the other 4 were negative. The bioassay was negative for 1 patient; the other died unrelated to PRCA before testing. Follow-up with RIP testing after 15 months under continuous epoetin treatment was negative (4 patients, 2 deceased).. This survey did not identify anti-erythropoietin antibodies in hemodialysis patient's hyporesponsive to epoetin and does not support presumptive antibody screening as a routine work-up in these patients.

Topics: Aged; Anemia; Antibodies; Cohort Studies; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Male; Middle Aged; Radioimmunoprecipitation Assay; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Renal Insufficiency

Topics: Erythropoietin; Fibrosis; Gadolinium; Humans; Recombinant Proteins; Renal Insufficiency; Skin Diseases

Nephrogenic systemic fibrosis is a rare fibrosing condition that occurs in patients with renal insufficiency. While its histologic characteristics have been well described, the etiology and pathogenesis have not been fully characterized. Several recent studies support the theory that gadolinium-based contrast agents play a causative role in the development of the disease. Erythropoietin therapy and endothelial damage from surgical procedures have also been suggested as potential contributing factors.. This study attempts to help contribute to the understanding of this novel disorder.. We performed a retrospective chart review of 6 patients diagnosed with nephrogenic systemic fibrosis at our institution. Emphasis was placed on identification of potential putative etiologic agents including gadolinium, erythropoietin therapy, and previous surgical procedures.. All patients had documented exposure to gadolinium-based contrast agents. Three of the 6 patients were treated with erythropoietin, and all patients underwent a previous surgical procedure.. This study is limited by its small size; therefore, the findings and results may not be applicable to all patients with this disorder.. Our data suggest that gadolinium plays a primary role in nephrogenic systemic fibrosis and that prior surgery may be a contributory factor.

Topics: Adult; Aged; Contrast Media; Erythropoietin; Female; Fibrosis; Gadolinium; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Skin Diseases; Surgical Procedures, Operative

An 18-year-old woman patient was discovered to have severe anemia and advanced renal failure during a routine prenatal follow-up at her 6th week of gestation. During the first few weeks of therapy, the hemodialysis frequency was increased gradually and Erythropoietin was administered with intravenous iron therapy to keep the patient's hemoglobin above 115 gm/L. Blood pressure rose was controlled by alpha methyldopa. Obstetric follow-up consisted of monitoring the fetal activity and growth, placental maturity and umbilical artery perfusion. On the 32nd week of gestation, the patient had a normal vaginal delivery of live female weighing 2,100 gm. the patient had a completely uneventful postpartum course and the newborn baby was well. In conclusion, our index case illustrates that intensified dialysis regimens and attentive medical care results in a successful outcome of pregnancy in patients with end stage renal disease on hemodialysis.

Topics: Adolescent; Anemia, Iron-Deficiency; Erythropoietin; Female; Follow-Up Studies; Humans; Infant, Newborn; Iraq; Iron; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Renal Dialysis; Renal Insufficiency

Despite the universal availability of erythropoietin and intravenous iron, 14% of transplant patients and 30% of dialysis patients have a haemoglobin (Hb) <10.5 g/dl. Only 11% of anaemic transplant patients were receiving erythropoietin. There was a linear relationship between estimated glomerular filtration rate (eGFR) and Hb with the risk of anaemia occurring at a much higher eGFR than would be expected in the chronic kidney disease (CKD) population. There was also a significant association between the use of mycophenolate and anaemia. Around 95% of dialysis patients were receiving erythropoietin and 47% intravenous iron. It is speculated that raising the target Hb for this population to 13 g/dl could shift the whole distribution curve to the left, reducing the proportion with anaemia. Doing this would require careful monitoring to steepen the distribution curve and limit the upper tail if complications of high haematocrits are to be avoided.

Topics: Adolescent; Anemia; Child; Child, Preschool; Erythropoietin; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Registries; Renal Insufficiency; Renal Replacement Therapy; Risk Factors; United Kingdom

Anemia after heart transplantation is common; however, there are scant data on etiology and treatment. This study evaluates type of anemia and the effects of erythropoietin therapy.. In 37 anemic heart transplant recipients (31 male/59.1+/-10.3 years/hemoglobin <12.0 g/dl), complete anemia work-up was performed including erythropoietin determination. For three months, 12 anemic patients with renal failure (9 male/64.1+/-13.6 years) were treated with 1-3x4000 IU of epoietin beta/week; treatment endpoints were hemoglobin levels and quality of life as determined by questionnaire.. In 31 patients no other cause of anemia than renal insufficiency (mean creatinine 1.9+/-0.9 mg/dl, mean calculated GFR 50.8+/-21.5 ml/min, no hemodialysis) was found; in 93.5% of these patients with renal insufficiency, measured erythropoietin levels were markedly lower than predicted [Beguin Y, Clemons GK, Pootrakul P, Fillet G. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 1993; 81(4):1067-1076.]. There was an inverse correlation of hemoglobin levels with serum creatinine/creatinine clearance and a strong trend for inverse correlation of erythropoietin levels. All 12 patients treated with erythropoietin showed a significant increase in hemoglobin levels after three months returning to pre-treatment values within 3 months of cessation of therapy (before study 10.8+/-1.1 g/dl, end of study 14.1+/-1.7 g/dl, three months after end of study 11.6+/-2.1 g/dl; p<0.005). Quality of life was significantly improved in eight patients (75%).. Anemia after heart transplantation is associated with moderate renal failure and low erythropoietin levels in most patients. Erythropoietin therapy resulted in increased hemoglobin levels in all and improved quality of life in 75% of patients. Erythropoietin may be a superior marker of functional renal impairment after heart transplantation; its therapeutic substitution allows effective anemia management and improves quality of life.

Topics: Aged; Anemia; Creatinine; Erythropoietin; Female; Heart Transplantation; Humans; Male; Middle Aged; Pilot Projects; Postoperative Complications; Quality of Life; Recombinant Proteins; Regression Analysis; Renal Insufficiency

The goal of this research was to develop a strategy to couple stem cell and gene therapy for in vivo delivery of erythropoietin (Epo) for treatment of anemia of ESRD. It was shown previously that autologous bone marrow stromal cells (MSCs) can be genetically engineered to secrete pharmacologic amounts of Epo in normal mice. Therefore, whether anemia in mice with mild to moderate chronic renal failure (CRF) can be improved with Epo gene-modified MSCs (Epo+MSCs) within a subcutaneous implant was examined. A cohort of C57BL/6 mice were rendered anemic by right kidney electrocoagulation and left nephrectomy. In these CRF mice, the hematocrit (Hct) dropped from a prenephrectomy baseline of approximately 55% to 40% after induction of renal failure. MSCs from C57BL/6 donor mice were genetically engineered to secrete murine Epo at a rate of 3 to 4 units of Epo/10(6) cells per 24 h, embedded in a collagen-based matrix, and implanted subcutaneously in anemic CRF mice. It was observed that Hct increased after administration of Epo+MSCs, according to cell dose. Implants of 3 million Epo+MSCs per mouse had no effect on Hct, whereas 10 million led to a supraphysiologic effect. The Hct of CRF mice that received 4.5 or 7.5 million Epo+MSCs rose to a peak 54+/-4.0 or 63+/-5.5%, respectively, at 3 wk after implantation and remained above 48 or 54% for >19 wk. Moreover, mice that had CRF and received Epo+MSCs showed significantly greater swimming exercise capacity. In conclusion, these results demonstrate that subcutaneous implantation of Epo-secreting genetically engineered MSCs can correct anemia that occurs in a murine model of CRF.

Topics: Anemia; Animals; Bone Marrow Cells; Disease Models, Animal; Erythropoietin; Female; Genetic Engineering; Mice; Mice, Inbred C57BL; Renal Insufficiency; Retroviridae; Stem Cells; Stromal Cells

The effects of erythropoietin (EPO) treatment on the immune functions of dialysis patients have been shown to be controversial and there are only limited data concerning predialysis patients.. Twenty-four predialysis patients with renal anemia were assigned to subcutaneous EPO treatment, and those in need (n=19) were additionally treated with i.v. iron every other week. We analyzed the effect of the start of EPO treatment on (i) lymphocyte and lymphocyte subclass counts, (ii) lymphocyte stimulation functions and (iii) persisting IgG-class antibody levels to the viral antigens of Epstein-Barr virus and cytomegalovirus.. Our main findings were a decrease in the absolute lymphocyte count, combined with decreases in all the main lymphocyte subclass counts. The absolute number of cells with activation and memory markers remained constant, and therefore their proportion slightly increased. The proliferation responses to phytohemagglutinin, tuberculin and tetanus declined significantly, while the amount of IgG-class viral antibodies remained unchanged, meaning that the humoral side of immunity was not affected by the start of the EPO treatment. Similarly, the proliferation response to pokeweed mitogen, a B-cell mitogen, was unchanged.. EPO treatment has a suppressive effect on cellular immune functions of predialysis patients. This suppression does not correlate with erythropoiesis, kidney function or iron status.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Humans; Immunity, Cellular; Lymphocyte Activation; Lymphocytes; Middle Aged; Renal Dialysis; Renal Insufficiency

Topics: Erythropoietin; Fibrosis; Humans; Recombinant Proteins; Renal Insufficiency; Skin Diseases

Topics: Anemia; Erythropoietin; Humans; Renal Insufficiency

Recombinant erythropoietin upregulates the expression of the vascular endothelial growth factor (VEGF) receptors, Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), in endothelial cells. The integrity of the VEGF system seems to be crucial for the regulation of endothelial permeability and thus for the avoidance of renal protein leakage. As albuminuria/proteinuria is a hallmark of diabetic nephropathy, we examined cross-sectionally in 35 type 1 and 37 type 2 diabetic patients with various degrees of renal dysfunction and albuminuria whether there was an interrelationship between intrinsic erythropoietin (EPO) and VEGF/Flt-1.. In patients with plasma creatinine values < or =1.5 (n = 53) or >1.5 mg/dL (n = 19), the mean serum EPO was 5.6 +/- 4.4 and 10.2 +/- 7.0 mU/mL (P = 0.02), respectively. In the two groups, urinary and serum VEGF(165) concentrations were similarly distributed (mean 94.3 +/- 91.8 vs 108 +/- 72.2 ng/L and 91.7 +/- 76.8 vs 91.9 +/- 74.9 ng/L, respectively; both P = NS). The mean urinary Flt-1 for the two groups amounted to 0.14 +/- 0.35 and 0.51 +/- 0.93 ng/mL (P = 0.045), respectively. No correlation between VEGF or Flt-1 and EPO was apparent.. Our data suggest that in vivo EPO does not affect the functionality and/or production of components of the VEGF/Flt-1 system in diabetics with normal or reduced renal function.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Anemia; Cross-Sectional Studies; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Renal Insufficiency; Solubility; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

A diabetic predialysis patient who had significantly reduced sensitivity to erythropoietin therapy was admitted to Tsukuba University Hospital. Many factors that might have been the cause of the erythropoietin resistance were examined, and a diagnosis of refractory anaemia was made based on a bone marrow aspiration biopsy. A cytogenetic abnormality (47, XXY) was also detected in the bone marrow biopsy specimen, and hence the patient was also diagnosed with Klinefelter syndrome. It was suspected that the sex chromosome abnormality influenced glucose intolerance, renal insufficiency, and erythropoietin resistance due to myelodysplastic changes in the bone marrow.

Topics: Anemia; Drug Resistance; Erythropoietin; Humans; Karyotyping; Klinefelter Syndrome; Male; Middle Aged; Renal Insufficiency

The percentage of hypochromic erythrocytes (%HYPO) and the reticulocyte hemoglobin content (CHr) have been used for the diagnosis of iron deficiency (ID). However, we found a discrepancy between %HYPO and CHr values in some hemodialysis patients. Hemodialysis patients receiving recombinant human erythropoietin (rHuEPO) with ID were defined as patients with a %HYPO value exceeding 5%. Five ID patients with a high CHr (group A) and 3 ID patients with a low CHr (group B) received 120 mg/week iron intravenously for 8 to 12 weeks. Changes in %HYPO, CHr, percentage of macrocytic erythrocytes (%MACRO), absolute reticulocyte count, immature reticulocyte fraction, and soluble transferrin receptor level were investigated over a 20-week period. CHrs were measured with 2 hematology analyzers: the Bayer HealthCare Technicon H*3 and the ADVIA 120. Patients in group A showed a significantly greater mean %MACRO (P < .01) and a lower mean red blood cell number (P < .05) than patients in group B. Even the mean CHr at baseline in group A was significantly higher than the mean CHr in the healthy subjects (P < .01), and hemoglobin levels increased in association with the reduction in rHuEPO dose following iron administration (P < .01). We found a group with high CHr, %HYPO, and %MACRO values among hemodialysis patients. Iron administration enables the rHuEPO dose to be reduced.

Topics: Anemia, Iron-Deficiency; Case-Control Studies; Drug Monitoring; Erythrocytes; Erythropoietin; Hematologic Tests; Hemoglobins; Humans; Iron; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Reticulocytes

Topics: Aged; Anemia; Anticoagulants; Diagnosis, Differential; Erythropoietin; Granulomatosis with Polyangiitis; Humans; Leg Ulcer; Male; Recombinant Proteins; Renal Insufficiency; Thrombosis; Treatment Outcome; Warfarin

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Humans; Renal Insufficiency

Anaemia is one of the most serious complications of renal dysfunction and is associated with severe, often life-threatening clinical sequelae including cardiovascular disease [1]. Anaemia of renal insufficiency originates from a reduced ability of the kidney to produce the protein hormone erythropoietin (EPO), which is responsible for the initiation of red blood cell (RBC) production from precursor cells produced by the bone marrow. Currently, European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure recommend that treatment of renal anaemia should be achieved by the supplementation of endogenous EPO with recombinant human EPO (rHuEPO), which stimulates erythropoiesis, thereby inducing a rise in haemoglobin (Hb) concentrations [2]. Usually, rHuEPO therapy is given two or three times per week and can be administered by the intravenous or subcutaneous routes in patients undergoing haemodialysis (HD) or subcutaneously in patients receiving peritoneal dialysis (PD). Darbepoetin alfa (Aranesp, Amgen, Inc.) is an erythropoiesis-stimulating protein that is molecularly distinct from rHuEPO. It is super-sialated, which leads to a longer serum half-life than that of rHuEPO [3,4], resulting in extended in vivo erythropoietic activity. Darbepoetin alfa can be given less frequently and can be used subcutaneously or intravenously with the same, or equivalent Hb responses and dosing [7], offering simplified dosing for new patients and those currently treated with rHuEPO. Clinical trials with darbepoetin alfa began in 1997 and this brief article reports on two patients whose long-term anaemia management has been simplified by its use.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Humans; Male; Peritoneal Dialysis, Continuous Ambulatory; Renal Insufficiency

In patients with cirrhosis, anemia is common and is likely to be multifactorial, including decreased erythrocyte production, sequestration due to hypersplenism, hemolysis, and increased blood loss from gastrointestinal bleeding. Renal dysfunction is also common in liver disease and this may also cause anemia. However, an association between anemia and renal dysfunction has not been reported in patients with cirrhosis. Our objective was to determine whether anemia in cirrhotic patients is independently related to renal dysfunction. We conducted a retrospective chart review of patients in our institution listed for liver transplantation. We collected simultaneous data on age, hemoglobin, creatinine, albumin, liver enzymes, prothrombin time, and bilirubin. We excluded patients who were hospitalized or deceased to avoid confounding variables. Two hundred eighty-six (female n = 130) patients with a mean age of 52.8 +/- 9.7 (range, 18-73) years were studied. Renal dysfunction (creatinine > 1.2 mg/dL) was present in 55 (19%) patients, and anemia (hemoglobin < 12 g/dL) was seen in 115 (40%) patients. Anemia was more common in patients with renal dysfunction (64 versus 34%; P < 0.001) compared to those with normal renal function. Creatinine, prothrombin time, and bilirubin showed an inverse relationship (all P's < 0.001) with hemoglobin, and albumin showed a positive correlation with hemoglobin (P < 0.001). Multivariate analysis showed that creatinine (OR, 2.4; 95% CI, 1.05-5.3; P = 0.038), prothrombin time (P = 0.026), bilirubin (P = 0.035), and albumin (P = 0.001) were independent predictors of anemia. Renal dysfunction is an important cause of anemia in patients with cirrhosis. The role of erythropoietin in the management of anemia in patients with cirrhosis and renal dysfunction should be explored in prospective studies.

Topics: Adolescent; Adult; Age Distribution; Aged; Analysis of Variance; Anemia; Chronic Disease; Comorbidity; Confidence Intervals; Erythropoietin; Female; Follow-Up Studies; Humans; Incidence; Kidney Function Tests; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Odds Ratio; Probability; Renal Insufficiency; Retrospective Studies; Risk Assessment; Sex Distribution; Waiting Lists

It was hypothesized that pentoxifylline might improve the response to recombinant human erythropoietin (rh-Epo) in anemic renal failure patients. Sixteen patients with ESRD and rh-Epo-resistant anemia, defined by a hemoglobin of <10.7 g/dl for 6 mo before treatment and a rh-Epo dose of > or =12,000 IU/wk, were recruited. They were treated with oral pentoxifylline 400 mg o.d. for 4 mo. Ex vivo T cell generation of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) from the patients was assessed before treatment and 6 to 8 wk after therapy. A total of 12 of 16 patients completed the study. Before therapy, the 12 patients' mean hemoglobin concentration was 9.5 +/- 0.9 g/dl. After 4 mo of pentoxifylline treatment, the mean hemoglobin concentration increased to 11.7 +/- 1.0 g/dl (P = 0.0001). Baseline ex vivo T cell expression of TNF-alpha decreased from 58% +/- 11% to 31% +/- 23% (P = 0.0007) after therapy. Likewise, IFN-gamma expression decreased from 31% +/- 10% to 13% +/- 10% (P = 0.0002). Pentoxifylline therapy may significantly improve the hemoglobin response in patients with previously rh-Epo-resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production, which could interfere with the effectiveness of rh-Epo.

Topics: Adult; Aged; Anemia; Cytokines; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Flow Cytometry; Free Radical Scavengers; Hemoglobins; Humans; Inflammation; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Pentoxifylline; Recombinant Proteins; Renal Insufficiency; T-Lymphocytes; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

A 73-year-old man, a 73-year-old woman, and a 57-year-old man with anaemia due to renal insufficiency were treated with epoetin. After 6-12 months, the haemoglobin level decreased despite dosage increases, after which the patients became dependent on regular transfusions of concentrated erythrocytes. The older man died from peritonitis following diagnostic examination because of the anaemia. The woman died from septic shock, even though epoetin had been replaced by darbepoetin. The haemoglobin level in the younger man returned to normal after the presence of antibodies against epoetin had been demonstrated, he had stopped using the drug, and he had started on immunosuppressive therapy following kidney transplantation. Since 1998, the number of patients with epoetin resistance due to the development of antibodies against the drug (epoetin-induced pure red-cell aplasia) has increased. This complication should be considered in every patient treated with epoetin who experiences unexplained transfusion-dependent anaemia.

Topics: Aged; Anemia; Antibodies; Drug Hypersensitivity; Erythrocyte Transfusion; Erythropoietin; Fatal Outcome; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency

One of the complications of hemodialysis (HD) therapy is anemia caused by erythropoietin (EPO) deficiency. Recombinant EPO (rEPO) has been used routinely as a supplemental treatment. Erythrocyte expression of the complement regulatory proteins decay accelerating factor (DAF) and CD59 restricts complement activation and inhibits hemolysis. We hypothesized that the efficacy of rEPO treatment may be caused in part by the ability of rEPO to increase erythrocyte expression of DAF and CD59.. DAF, CD59, and complement receptor 1 (CR1) levels were analyzed for a group of 95 HD patients and compared with those of a control group. To evaluate effects of discontinuation of rEPO therapy, rEPO therapy was stopped for 12 HD patients until hematocrits decreased to less than 25%. DAF and CD59 levels then were reanalyzed.. In the 95 HD patients, three factors correlated significantly: DAF and CD59 (r = 0.642), DAF and CR1 (r = 0.503), and CD59 and CR1 (r = 0.324), whereas no correlations were found in the group of 42 healthy controls. In the experiment in which rEPO therapy was discontinued, 8 of 12 patients reached the defined level of anemia 4 to 7 weeks after rEPO treatment had been withheld. Both DAF and CD59 levels decreased significantly after discontinuation of rEPO therapy (P < 0.01). DAF and CD59 levels increased in all 8 patients after rEPO treatment was reinitiated (P < 0.01), and CR1 levels increased in 5 of 8 patients. Four of 12 patients showed no evidence of anemia after discontinuation of rEPO treatment. In these patients, DAF, CD59, and CR1 levels did not change before or after withholding rEPO therapy.. One of the mechanisms mediating the efficacy of EPO therapy is increased DAF and CD59 expression.

Topics: Anemia; CD55 Antigens; CD59 Antigens; Chronic Disease; Complement C3; Diabetes Mellitus; Erythrocytes; Erythropoietin; Glomerulonephritis; Humans; Middle Aged; Receptors, Complement; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

At birth, undescended testes contain germ cells, but after 1 year of life, a reduced number of germ cells is generally found. Microlithiasis and carcinoma-in-situ-testis occur in cryptorchid boys. Multinucleated germ cells, including at least 3 nuclei in the cell, exist in impaired spermatogenesis and in the senescent testis.. We investigated whether multinucleated spermatogonia were present in undescended testes of cryptorchid boys, and if such a pattern is associated with special clinical features.. Multinucleated spermatogonia occurred in 13/168 (8%) of 163 consecutive cryptorchid boys, who underwent surgery for cryptorchidism with simultaneous testicular biopsy showing seminiferous tubules. The patients with multinucleated spermatogonia more often exhibited a normal germ cell number (Fisher's exact test, p<0.0005), and were younger at surgery (Mann Whitney, p<0.005) than the rest of the patients. Before surgery, 3 patients underwent treatment with Erythropoietin because of renal failure. An intra-abdominal testis underwent clipping and division of the spermatic vessels, and a biopsy at final surgery 7 months later, exhibited multinucleated spermatogonia. In 1 case the undescended testicular position, a fixed retraction, was acquired after surgery for an inguinal hernia. Multinucleated spermatogonia were found in cases of carcinoma-in situ-testis in 2 cryptorchid boys. No case of multinucleated germ cells appeared in our normal material.. Multinucleated spermatogonia are a further abnormality present in cryptorchidism. The cryptorchid boys with multinucleated spermatogonia in general exhibited rather many germ cells. This feature may be associated with an increased risk of testicular malignancy later in life, and we propose a careful follow up regime in these cases including ultrasound examination and a testicular biopsy in cases of symptoms or clinical findings.

Topics: Biopsy; Carcinoma in Situ; Cell Nucleus; Child; Child, Preschool; Cryptorchidism; Erythropoietin; Humans; Infant; Male; Precancerous Conditions; Renal Insufficiency; Risk Factors; Spermatogonia; Testicular Neoplasms

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Humans; Renal Dialysis; Renal Insufficiency

Topics: Anemia; Contraindications; Epoetin Alfa; Erythroblasts; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency

Although posttransplant anemia (PTA) is recognized as a common problem in adult renal transplant recipients, few pediatric studies have been published.. In this retrospective cohort study of 162 pediatric renal transplant recipients treated at Stanford University, the authors sought to determine the prevalence, severity, and the predictive factors of PTA. Anemia was defined as a hematocrit (HCT) level greater than 2 SD below published means for age or as erythropoietin dependency to maintain a normal HCT.. Sixty-seven percent of pediatric renal transplant recipients were anemic at the time of transplantation. The prevalence of anemia increased to 84.3% in the first month posttransplant. From 6 months to 60 months posttransplant, the prevalence of anemia remained high at 64.2% to 82.2%. Only 4 patients (2.5%) were never anemic. Iron depletion was detected in 19 of 26 and 23 of 23 anemic patients 12 and 60 months posttransplant, respectively. Serum erythropoietin levels were low relative to hematocrit levels in 38 of 56 anemic patients. Logistic regression at 3 months posttransplant showed that discharge hematocrit level (P < 0.0001), calcium (P = 0.0004), and cyclosporine dose (P = 0.0002) correlated with anemia. Creatinine clearance (P = 0.002) and white blood cell count (P = 0.004) correlated with anemia at 12 months posttransplant, but only creatinine clearance (P = 0.011) correlated with anemia 60 months posttransplant.. Nearly all pediatric renal transplant recipients experience PTA. However, few children less than 2 years of age were anemic during the first year posttransplant. Antirejection therapy, bone disease, iron depletion, and creatinine clearance appear to play pivotal roles in the development of PTA in children.

Topics: Adolescent; Anemia; Child; Child, Preschool; Cohort Studies; Creatinine; Erythropoietin; Female; Humans; Infant; Iron; Kidney; Kidney Transplantation; Logistic Models; Male; Predictive Value of Tests; Prevalence; Renal Insufficiency; Retrospective Studies; Risk Factors; Severity of Illness Index

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

Topics: Adult; Age Factors; Anemia; Anemia, Hemolytic; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferritins; Humans; Japan; Male; Middle Aged; Myelodysplastic Syndromes; Reagent Kits, Diagnostic; Receptors, Transferrin; Recombinant Proteins; Renal Insufficiency; Sex Factors; Solubility

American guidelines for the management of renal anemia by recombinant human erythropoietin (rHuEPO) recommend collecting a predialysis blood sample to evaluate hemoglobin (Hb) and hematocrit (Hct) levels in hemodialysis patients. Although a predialysis blood sample is appropriate for evaluating when to start rHuEPO treatment, the same sample would not be appropriate for evaluating the target Hb/Hct to be maintained, particularly when normal or near-normal values are pursued. We measured the degree of intradialytic and extradialytic variation of Hb, Hct, and body weight in 68 stable hemodialysis patients on maintenance subcutaneous rHuEPO treatment. Hb and Hct concentrations were determined before and after dialysis. In 16 patients, Hb and Hct concentrations also were assessed 24 hours after the end of dialysis. Predialysis versus postdialysis Hb and Hct concentrations for all patients were 10.5 +/- 1.3 g/dL versus 11.5 +/- 1.3 g/dL (P < 0.0001) and 32 +/- 4% versus 35 +/- 4% (P < 0.0001). The intradialytic percent variation (%Delta) of Hct and body weight were 10 +/- 6% and -6.3 +/- 3.5%. There was a close inverse correlation between %Delta of Hct and Hb and %Delta of body weight (P < 0.0001). In patients with body weight losses 2.5 kg or more per session, the mean %Delta of Hct was 12 +/- 7%. In the 16 patients studied 24 hours after the end of the dialysis session, Hct and Hb values remained significantly higher compared with the predialysis levels (P < 0.001), suggesting a slow reequilibration of the intravascular volume in the first 24 hours after hemodialysis. For these reasons, predialysis samples for monitoring the target Hb and Hct levels in patients treated by rHuEPO should be considered with caution.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

Topics: Anemia; Epoetin Alfa; Erythroblasts; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Iron; Recombinant Proteins; Renal Insufficiency

Erythropoietin (EPO) is recommended in individuals progressing toward end-stage renal disease (ESRD) to correct anemia and its complications, which are common in this disease. This study evaluated the impact of EPO administered before dialysis on mortality in incident ESRD patients. A total of 4,866 patients whose exposure to pre-ESRD EPO was determined from Health Care Financing Administration 2728 forms were analyzed. The median follow-up was 26.2 months, with 1,107 (22.7%) patients given EPO and 1,892 (38.9%) deaths. EPO use was more common in patients who had insurance before dialysis, remained employed, were started on renal replacement therapy outside the hospital, or initiated on peritoneal dialysis, which could be indicative of early intervention or quality care. The risk of death after starting dialysis was lower for patients treated with EPO before dialysis compared with patients who were not treated (adjusted relative risk 0.80, 95% confidence interval 0.70 to 0.91). There was no direct relationship between predialysis hematocrit and mortality; however, the most significant survival benefit with EPO use was in patients with the highest hematocrit values (adjusted relative risk 0.67, 95% confidence interval, 0.51 to 0.89). The most significant effect of pre-ESRD EPO use was observed during the first 19 months after starting dialysis (adjusted relative risk, 0.81; 95% confidence interval, 0.71 to 0.91), but this benefit diminished in patients with longer follow-up on renal replacement therapy. Use of EPO before dialysis confers a survival benefit to ESRD patients, especially in patients with an adequate hematocrit response before initiation of dialysis.

Topics: Aged; Anemia; Cohort Studies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Renal Dialysis; Renal Insufficiency; Retrospective Studies; Risk; Survival Analysis

Topics: Blood Donors; Blood Transfusion, Autologous; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Fees, Pharmaceutical; Hematinics; HIV Infections; Hypertension, Renal; Neoplasms; Premedication; Preoperative Care; Recombinant Proteins; Renal Insufficiency

15 years after recombinant erythropoietin (EPO) has become available for the treatment of renal anemia, the target hemoglobin concentration to be achieved is still controversial. A positive impact of partial correction of renal anemia on quality of life has been conclusively demonstrated. Several more recent studies indicate that further improvement of well-being can be achieved with normalization of hemoglobin levels. In addition, there is increasing evidence that anemia is associated with the progression of left-ventricular hypertrophy and mortality. These findings imply that correction of renal anemia has the potential to improve patient prognosis. However, in patients with advanced cardiac disease, the US normal hematocrit failed to demonstrate a prognostic benefit and instead suggested that the attempt to normalize hemoglobin may be harmful. Nevertheless, in patients with less advanced cardiac disease complete correction of renal anemia may prevent progressive ventricular dilatation. The impact of early anemia correction is currently tested in several trials in predialysis patients. Irrespective of the uncertainties about the upper target range, current US and European guidelines have defined a hemoglobin concentration of 11 g/dl as the lower target range on the basis of both symptomatic and prognostic considerations. In the majority of patients these minimum requirements are not yet achieved. Less then 10% of patients receive EPO prior to the onset of dialysis, the mean hemoglobin level at the start of dialysis is not higher than 9 g/dl and a significant proportion of patients permanently remain below 11 g/dl.

Topics: Aged; Anemia; Erythropoietin; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Renal Insufficiency

Renal failure continues to carry substantial burden of morbidity and mortality in both acute and chronic forms, despite advances in transplantation and dialysis. There is evidence to suggest that the kidney has metabolic, endocrine, and immune effects transcending its filtration functions, even beyond secretion of renin and erythropoietin. Our laboratory has developed experience in the tissue culture of renal parenchymal cells, and has now been able to demonstrate the metabolic activity of these cells in an extracorporeal circuit recapitulating glomerulotubular anatomy. We have observed active transport of sodium, glucose, and glutathione. We describe the design and initial preclinical testing of the bioartificial kidney, as well as future directions of our research.

Topics: Animals; Bioartificial Organs; Bioreactors; Cells, Cultured; Erythropoietin; Kidney Tubules, Proximal; Kidneys, Artificial; Renal Insufficiency; Renin

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

Succesful results in the treatment of anemia, one of the main complications of chronic renal failure, can be achieved by the use of recombinant human erythropoietin (RhEPO), which is available almost fifteen years in clinics. On the other hand, as both chronic renal failure and maintenance hemodialysis reduce the levels of trace elements, this study was designed to evaluate the interaction potential of RhEPO with serum concentrations of selenium (Se) during four months. Thirty one adult hemodialysis outpatients participated in the study. Ten of them, not on any drug therapy to interact with RhEPO, recruited as "Control Group", and the remainder, on RhEPO therapy, as "RhEPO Group". Blood was drawn from the Control Group at the beginning of the study, and from the RhEPO Group at every month for four months. Serum erythropoietin leveLs were measured by a radioimmunoassay method and Se status by a spectrofluorometric method. It was found that Se levels were not affected by RhEPO treatment during 3 months of therapy, while an increase was seen on the fourth month. The observation indicates that the increase in serum Se levels would be significant in longer than three-month RhEPO treatment.

Topics: Adult; Age Factors; Aged; Erythropoietin; Female; Humans; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Selenium; Sex Factors; Time Factors

An enzyme-immunoassay was developed to evaluate the presence of anti-erythropoietin antibodies in plasma samples obtained from renal failure patients treated with recombinant human erythropoietin (rh-EPO). The assay was specific and reproducible. Normal donors had no antibodies to EPO, while 67% of treated patients were positive to the assay. While the specificity of anti-EPO IgG antibodies was high, their affinity for the antigen was low. This finding can be explained by the very small differences in the structure of rh-EPO compared to that of natural EPO. The assay described could be useful in evaluating the long-term effects of rh-EPO treatment on the control of anaemia in renal failure patients.

Topics: Anemia; Antibodies; Erythropoietin; Humans; Immunoenzyme Techniques; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Reproducibility of Results

Current guidelines suggest that anaemia due to erythropoietin deficiency almost exclusively occurs with creatinine concentrations of at least 177 micromol/l or above. The aim of this prospective case control pilot study was to evaluate whether borderline renal function or mild renal dysfunction with creatinine concentrations well below 177 micromol/l is sufficient to induce inadequate erythropoietin secretion. Patients referred for work-up of otherwise unexplained anaemia with mildly abnormal creatinine concentrations (104-129 micromol/l; study group: eight patients) and patients referred for work-up or therapy of other diseases who also presented with anaemia but normal creatinine levels (<100 micromol/l; control group: nine patients matched for gender, age and degree of anaemia) were included. All but two patients in the control group had bone marrow biopsies to exclude other pathologies. Mild renal dysfunction (as evidenced by creatinine concentrations between 100 and 140 micromol/l, median concentration 112 micromol/l) was found to be sufficient to induce inadequate erythropoietin secretion. The physiologic hemoglobin-dependent erythropoietin regulation demonstrated in the control group was abolished in the study group. Patients with mild renal dysfunction and unexplained anaemia should be investigated for erythropoietin concentration. If the erythropoietin concentration is found to be inadequate for the degree of anaemia, substitution therapy should be considered.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Case-Control Studies; Creatinine; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Renal Insufficiency

Cystic renal lymphangiectasia is an unusual cause of cystic renal disease in childhood. We present a case of bilateral cystic renal lymphangiectasia in a 7-year-old boy who presented with asymptomatic renal insufficiency and anemia with decreased erythropoietin production. The clinical features of this condition and the diagnostic approach are reviewed. Although rare, this disorder should be considered in the differential diagnosis of cystic renal disease.

Topics: Anemia; Biopsy; Child; Diagnosis, Differential; Erythropoietin; Humans; Kidney; Kidney Diseases, Cystic; Lymphangiectasis; Male; Renal Insufficiency

To investigate the effects of erythropoietin (EPO) gene transfer into skeleton muscle mediated by electroporation on renal anemia.. Renal failure models were created by adenine-excessive diet (150 mg per day). Plasmid vectors encoding EPO were transferred by electroporation after 80 days when mean blood urea nitrogen level (BUN) had increased from 3.4 mmol/L +/- 1.3 mmol/L to 18.1 mmol/L +/- 4.1 mmol/L and the hematocrit had decreased from 45.6% +/- 2.1% to 25.4% +/- 3.7%. During the process of treatment, adenine-excessive diet was given. Hb, HCT, BUN and Cre in blood were tested by automatic analyzer; EPO level in the serum was tested by EPO ELISA kit, EPO gene expression was proved by RT/PCR. The survival rate was calculated.. Hematocrit increased to 34.4% +/- 7.5% only 7 days after the treatment and reached 91.4% of normal level (46% +/- 2%) after 5 weeks. The survival rate of test models after 9 weeks was 77.8%, which was remarkably higher than that of controls (16.7%). mRNA level of EPO gene expression was indicated by RT/PCR.. Electroporation can increase the efficiency of EPO gene transfer and thus greatly improve hematocrit in mice and prolong the life-span of chronic renal anemia models. This method can provide a new way for treatment of EPO-responsive anemias.

Topics: Adenine; Anemia; Animals; Disease Models, Animal; Electroporation; Erythropoietin; Gene Expression; Gene Transfer Techniques; Hematocrit; Kidney; Muscle, Skeletal; Rats; Rats, Wistar; Renal Insufficiency

Erythropoietin (Epo) is a hormone-like glycoprotein regulating erythropoiesis. Under normal conditions Epo stimulates mitoses of the erythroid progenitors and precursors, decreases apoptosis, decreases "ineffective erythropoiesis" and stimulates the synthesis of the specific protein, haemoglobin. Epo producing cells in the kidney sense the O2 tension of kidney tissue and react to hypoxia with increased Epo production and to O2 saturation (polycythaemia) with decreased or completely abolished Epo production. Normal level of Epo in the serum is 3-20 mU/ml. If Epo production is functioning normally there exists a strict inverse correlation between serum Epo level and hematocrit: an exponential increase in Epo level can be observed if hematocrit decreases. Any damage in Epo production lead to inadequate production (e.g. renal anaemias). This paper analyses the Epo content of 278 serum samples assayed in the Laboratory of Experimental Bone Marrow Transplantation of the National Institute of Hematology and Immunology between August 1996 and December 1997 for their diagnostic value. Those samples are primarily discussed where Epo assay was meant to decide diagnosis of polycythaemia vera or those where decision of Epo treatment of anaemic patients depended on their serum Epo level.

Topics: Anemia; Apoptosis; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Male; Renal Insufficiency

Topics: Anemia; Erythropoietin; Hemoglobins; History, 17th Century; History, 18th Century; History, 19th Century; Humans; Iron; Renal Insufficiency

The aim of the work has to assess the effects of L-carnitine therapy on erythropoiesis and whole blood platelet aggregation. The studies were performed in 28 patients divided into 3 groups: I-group was given erythropoietin, II-group was given erythropoietin and L-carnitine, III-group was given L-carnitine. After 22 month of the therapy a statistically significant rise in hematocrit was observed in group III, improvement in muscle strength, a rise in free and total carnitine concentration was found in group II and III. There were no significant changes in urea concentration, platelet count and iron metabolism. Whole blood platelet aggregation induced by ADP, collagen and ristocetin was impaired relative to healthy volunteers. After 2 month of L-carnitine treatment of significant rise in collagen induced platelet aggregation was observed in group II.

Topics: Adult; Carnitine; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Platelet Aggregation; Renal Dialysis; Renal Insufficiency

Topics: Anemia; Anemia, Hypochromic; Erythropoietin; Ferritins; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins; Renal Insufficiency

Topics: Anemia; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Renal Insufficiency

To determine the spectrum of serum immunoreactive erythropoietin (SIE) levels amongst HIV-infected children aged < 13 years in relation to the levels among healthy children as well as those with renal failure; to examine the relationship between clinical and laboratory parameters and SIE levels.. A cross-sectional study with a descriptive non-interventional format. HIV-infected Canadian subjects were recruited through four tertiary Canadian and one Bahamian centre. Children with renal failure and healthy children were recruited from one of the Canadian centres.. Study subjects had clinical and laboratory profiles determined at baseline and at each of five follow-up periods over 1 year. SIE levels were measured by radioimmunoassay with a normal range of 12-28 IU/I. Data handling and statistical functions were performed by the Canadian HIV Trials Network.. The study enrolled 133 HIV-infected subjects and 38 controls. Of these, 117 HIV-infected subjects, 24 healthy controls, and 11 controls with renal failure were eligible for analysis. The median age of infected subjects was 44 months, whereas that of healthy controls was 56 months, and 95 months for controls with renal failure. The median SIE levels were 14 and 11 IU/I for subjects with renal failure and healthy subjects, respectively. The median SIE level was 61 IU/I among zidovudine (ZDV)-treated subjects and 22 IU/I among ZDV-naive HIV-infected subjects. HIV-infected children almost invariably had SIE levels < 200 IU/I. The median SIE levels amongst HIV-infected subjects whose hemoglobin levels were < 100 g/l were 98 and 31 IU/I for ZDV-treated and ZDV-naive subjects, respectively (P = 0.002). This difference in median SIE levels between ZDV-treated subjects and ZDV-naive subjects was also observed among subjects whose hemoglobin levels were > 100 g/l (median, 58 and 15 IU/l, respectively; P < 0.001). Hemoglobin level was the most important predictor of log10 SIE (P < 0.01 for ZDV-treated and ZDV-naive subjects).. SIE levels amongst HIV-infected children were affected by HIV infection, use of ZDV, and presence or absence of anemia. SIE levels amongst HIV-infected children were generally lower than 200 IU/I. This characterization of SIE levels will facilitate clinical trials of exogenous recombinant human erythropoietin in HIV-infected children with anemia.

Topics: Anemia; Anti-HIV Agents; Bahamas; Canada; Child; Child, Preschool; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; HIV Infections; Humans; Infant; Male; Renal Insufficiency; Zidovudine

To establish a pharmacodynamic model that allows one to predict the haemoglobin (Hb) response to EPO in children as a function of dose and time, and to derive recommendations for initial dosing and subsequent dose adjustment.. Haemoglobin was monitored in eight children aged 8-15 years with anaemia due to renal failure during treatment with EPO. All patients were free of conditions known to impair the response to EPO. Pretreatment Hb was 4.9-9.0 g dl(-1). The drug was administered once weekly by subcutaneous injection; doses ranged from 1700 to 6800 U week (-1). Hb was monitored for 4-38 months. The Hb-time data were analysed by applying a population pharmacodynamic model proposed for EPO in adult haemodialysis patients. Internal model validation was carried out by using a bootstrap procedure.. The increase of Hb during treatment with EPO was linear until steady state was reached after 103+/-33 days (mean +/- interindividual s.d.). The weekly gain in Hb from the onset of therapy to steady state was 0.0805+/-0.026 g dl(-1) (mean +/- interindividual s.d.) for every 1000 U EPO week (-1); it did not exhibit a dependence on body weight. Estimated mean prediction errors are +/-1.53 g dl(-1) for predictions that are based on the mean population parameters and +/-0.83 g dl(-1) for predictions that take into account the complete individual Hb-time data up to and including steady state.. The model describes the time course of the Hb response to EPO in children with renal anaemia. The required weekly EPO dose should initially be calculated from the individual pretreatment Hb and the desired Hb at steady state by using the mean population estimates of the weekly gain in Hb per dose unit before steady state (beta) and the time needed to reach steady state (tau). A reduction of the initial dose according to body weight is not justified by the available evidence. beta should be re-estimated individually after 6 weeks of treatment and dose should be adjusted accordingly. A final dose adjustment should be made when steady state has been reached based on individual estimates of beta and tau.

Topics: Adolescent; Anemia; Body Weight; Child; Erythropoietin; Female; Hemoglobins; Humans; Male; Renal Insufficiency; Time Factors

We describe two patients admitted to our hospital because of renal failure. We diagnosed multiple myeloma in both. One patient had high peripheral blood eosinophilia, that normalized during therapy. The patients were treated with melphalan and prednisone, hemodialysis and one patient with recombinant human erythropoietin. Both patients responded to that treatment: after 7 months the number of plasma cell in bone marrow decreased from 65 to 10% in the first patient, and from 38 to 4% in the second patient. They returned to work and were on maintenance hemodialysis 2 times weekly. The patients have been observed for 21 months.

Topics: Aged; Erythropoietin; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Beginning in 1966, the Patient Registration Committee of the Japanese Society for Dialysis Therapy has conducted a survey once a year on renal replacement therapy in Japan. As of 1983, the survey covered the life/death of patients in the survey years, as well as the case mix of individual patients. In 1990 several laboratory variables were added to the survey items. The present report summarizes the data from the 1993 and 1994 surveys. The Committee mailed out questionnaire forms at the end of the survey year to the heads of all dialysis facilities. Survey forms were returned from 99.6% of the dialysis facilities in the 1993 survey, and from 99.8% of the facilities in the 1994 survey. Some 143709 patients were treated by renal replacement therapy in 1994 (7509 were treated by CAPD, and 131016 by extracorporeal haemopurification). The gross mortality rate was 9.5% in the same year. The mean values of the laboratory variables among 88693 patients undergoing thrice weekly haemodialysis were as follows in 1993: Kt/V, 1.31 +/- 0.30; protein catabolic rate, 1.04 +/- 0.30 g/kg/day; haemodialysis time, 4.12 +/- 0.50 h. In 1994, the variables were: predialysis serum creatinine concentration, 11.54 +/- 2.85 mg/dl; predialysis serum albumin concentration, 3.91 +/- 0.55 g/dl; predialysis haematocrit, 28.69 +/- 4.36%.

Topics: Aged; Blood Pressure; Creatinine; Data Collection; Erythropoietin; Female; Hematocrit; Humans; Japan; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Renal Replacement Therapy; Serum Albumin; Societies, Medical; Survival Rate

The diurnal rhythm in the circulating serum levels of erythropoietin (EPO) were determined in a group of 20 adult clinically-healthy subjects, in a group of 10 patients with myeloma without renal impairment and 10 patients with myeloma and renal failure. Venous blood samples were drawn during the span of a whole day and every 4 hr, starting from midnight, for the measurement of serum EPO levels by radioimmunoassay (RIA). Statistical analysis was carried out by means of the "cosinor" method. Results show that the controls and the myeloma patients without renal insufficiency present significant (P < 0.05) circadian rhythms in serum EPO levels; no rhythm (P < 0.05) was detected in patients with myeloma and renal failure. Patients with myeloma and renal failure have significant (P < 0.05) lower mean daily levels and diurnal fluctuations of EPO than the other groups, whereas the patients with myeloma without renal involvement present higher (P < 0.05) mean daily levels and lower (P < 0.05) diurnal variations of EPO than controls; no differences (P > 0.05) exist between the groups regarding peaks of rhythms. These data confirm the existence of a physiological circadian rhythm in serum EPO concentrations, with maximum in the afternoon, and they suggest that renal failure is an important cause of anemia and loss of EPO circadian rhythm in patients with myeloma.

Topics: Aged; Circadian Rhythm; Erythropoietin; Female; Humans; Male; Middle Aged; Multiple Myeloma; Radioimmunoassay; Renal Insufficiency

Topics: Adolescent; Adult; Aged; Cause of Death; Child; Child, Preschool; Erythropoietin; Humans; Infant; Infant, Newborn; Middle Aged; Renal Insufficiency; Renal Replacement Therapy

The effects of recombinant human erythropoietin (rHuEPO) treatment on parathyroid function in patients on maintenance hemodialysis (HD) with secondary hyperparathyroidism (HPT) is poorly understood. We compared the levels of serum intact parathyroid hormone (PTH) and the suppressibility of PTH by intravenous calcium infusion before and after 12 weeks of rHuEPO treatment in 8 HD patients with secondary HPT. The suppressibility of PTH by calcium infusion in HD patients was also compared with that of normal subjects. After rHuEPO treatment, in HD patients hematocrit and hemoglobin levels increased significantly from 20.1 +/- 1.3% and 6.65 +/- 0.46 g/dl to 28.7 +/- 1.0% and 9.68 +/- 0.39 g/dl, respectively. The serum intact PTH levels did not change significantly (541.9 +/- 65.3 pg/ml before versus 572.9 +/- 75.3 pg/ml after rHuEPO treatment), nor did serum ionized calcium, phosphate, magnesium, aluminum, alkaline phosphatase, and 1.25(OH)2D levels. Calcium infusion significantly increased serum ionized calcium and suppressed serum PTH levels. However, the increment in serum calcium levels and the percent decrement of serum PTH showed no significant differences before and after rHuEPO treatment in HD patients. Elevations in serum calcium levels during calcium infusions were not significantly different between normal subjects and HD patients. However, the percent maximal decrement in serum PTH level was less in HD patients both before and after rHuEPO treatment than in normal subjects (-75.4 +/- 3.9 and -76.4 +/- 4.1% versus -91.4 +/- 1.4%). We conclude that rHuEPO treatment has no influence on parathyroid function in maintenance HD patients with secondary HPT. In addition, PTH secretion is less suppressed by calcium infusion in the same group of patients.

Topics: Adult; Alkaline Phosphatase; Aluminum; Blood Urea Nitrogen; Calcifediol; Calcium; Creatinine; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Magnesium; Male; Middle Aged; Parathyroid Glands; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Time Factors

Hepatitis C virus infection in chronic hemodialysis patients is associated with several unresolved problems. We report a 85 years old female patient in chronic hemodialysis and treated with erythropoietin, that during the course of an Herpes zoster, presented severe malaise, weight loss and muscle weakness. Two weeks later, a slight rise in serum transaminases was detected. The patient had negative antibodies for HIV and hepatitis C virus and negative hepatitis B surface antigen. A PCR test was positive for serum hepatitis C virus RNA. The patient's condition deteriorated and she died 7 days after admission. Erythropoietin administration, whose immunosuppressive effect has been reported previously, could have influenced the dismal outcome of this patient.

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Follow-Up Studies; Hepatitis C; Herpes Zoster; Humans; Renal Dialysis; Renal Insufficiency; Transfusion Reaction; Viremia

Topics: Adult; Anemia; Anuria; Combined Modality Therapy; Erythropoietin; Female; Humans; Hypertension; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Erythropoietin (EPO) levels in plasma from 124 clinically anemic dogs were determined by in vivo bioassay. In 81 anemic dogs with normal renal function, the concentration of plasma EPO showed a close correlation with the hemoglobin concentration. The plasma EPO level was obviously decreased in 43 anemic dogs with renal failure. Of these dogs with renal failure, 17 showed no detectable plasma EPO and resulted in the death of these dogs. In the remaining 26 dogs having detectable plasma EPO, the plasma concentration rate of EPO related to blood urea nitrogen and serum creatinine values.

Topics: Anemia; Animals; Blood Urea Nitrogen; Creatinine; Dog Diseases; Dogs; Erythropoietin; Female; Hemoglobins; Male; Neoplasms; Regression Analysis; Renal Insufficiency

Topics: Anemia; Erythropoietin; Female; Humans; Male; Recombinant Proteins; Reference Values; Renal Insufficiency; Reticulocyte Count; Reticulocytes; RNA

Topics: Adult; Creatinine; Cyclosporine; Erythropoietin; Female; Hemoglobins; Humans; Kidney Transplantation; Male; Postoperative Period; Prednisone; Radioimmunoassay; Renal Insufficiency; Reticulocyte Count; Time Factors; Tissue Donors; Transplantation, Homologous

Topics: Anemia; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency

Topics: Adenosine Diphosphate; Blood Platelets; Collagen; Erythropoietin; Humans; In Vitro Techniques; Platelet Aggregation; Platelet Count; Renal Dialysis; Renal Insufficiency

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

With a newly developed enzyme linked immunosorbent assay kit TOYOBO Co. in which 2 anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from normal adults, 168 patients with renal failure and 333 patients with hematological disorders. In the patients with renal failure, serum EPO level was normal (52.9%) or reduced (42.9%), and there was no correlation to their hematocrits. However, there was an increment in EPO concentration correlated to their severity of anemia in the most patients with hematological disorders, such as iron deficiency anemia (correlation coefficient r = -0.74), aplastic anemia (r = -0.89), leukemia (r = -0.81), and MDS (r = -0.65). On the other hand, EPO concentration in sera from all the untreated patients with polycythemia vera were significantly low level. But the concentrations of EPO from the patients successfully treated, with normal hematocrit were recovered to normal level. In the patients with secondary polycythemia, there were much varieties in EPO level. Assay of EPO in blood is important not only for diagnosis of polycythemia but also for the analysis of anemia and clinical use of EPO in vivo. The method described here is accurate and technically not complicated, and could be widely induced in most laboratories.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematologic Diseases; Humans; Male; Middle Aged; Renal Insufficiency

With a newly developed short term enzyme linked immunosorbent assay kit (TOYOBO Co.), in which 2 kinds of anti-EPO monoclonal antibodies were used, we assayed EPO concentration in sera from patients with renal failure and hematological disorders. In this report, the EPO data were analysed in relation to serum iron concentrations, with ferritin and UIBC. In the patients with renal failure, there was no significant correlation between EPO concentration and serum iron, ferritin, nor UIBC concentration. On the other hand, in the patients with hematological disorders, there were two types. One was in patients with iron deficiency anemia, whose serum EPO was negatively correlated to serum iron (r = -0.64) and ferritin (r = -0.59), but positively related to UIBC (r = 0.27). The another was the pattern in patients with aplastic anemia, leukemia and MDS, whose serum EPO positively correlated to iron and ferritin but negatively correlated to UIBC. In the patients with aplastic anemia serum EPO had good correlation to serum iron (r = 0.62), ferritin (r = 0.60) and UIBC (r = -0.46). The relationship of EPO to iron in the patients with leukemia (r = 0.54), and EPO to ferritin in the patients with MDS (r = 0.42) show significantly positive correlation coefficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Enzyme-Linked Immunosorbent Assay; Erythropoietin; Ferritins; Hematologic Diseases; Humans; Iron; Renal Insufficiency

The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.

Topics: Adolescent; Adult; Aged; Anemia; Bicarbonates; Erythropoietin; Exercise Tolerance; Female; Humans; Kidney Diseases; Lactates; Lactic Acid; Male; Middle Aged; Oxygen Consumption; Renal Dialysis; Renal Insufficiency

Recombinant human erythropoietin (r-HuEPO) was administered in 68 dialyzed patients (32 on acetate hemodialysis, 24 bicarbonate hemodialysis and 12 on hemo-filtration). The mean initial Hb 52.7 +/- 8.0g/L, Ht 19.4 +/- 2.2%, serum ferritin > 100ng/L. Each patients received r-HuEPO intravenously, at the dose of 300U/Kg/w for 6.2 +/- 4.3 months. Target range: Hb 100-120g/L, Ht 30-35%. After r-HuEPO treatment, blood transfusion was not needed for any of the patients, anemia was ameliorated with increase of Hb and Ht levels. It was found that the minimum effective dose of the r-HrEPO was 150-300U/Kg/w. We conclude that r-HuEPO is effective as treatment for the anemia of dialyzed patients. However, hypertension, clotted dialyzers and dialysis access thromboses were been developed in some patients after correction of anemia. There is now a general consensus that these side effects may be minimized if r-HuEPO is initially given in small doses with increments to avoid a too rapid correction of the anemia.

Topics: Adult; Anemia; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

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

Topics: Anemia; Blood Cell Count; Erythroid Precursor Cells; Erythropoietin; Hemoglobins; Humans; Immunologic Factors; Multiple Myeloma; Recombinant Proteins; Renal Insufficiency

Topics: Cardiovascular Diseases; Erythropoietin; Europe; Female; Graft Survival; Humans; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Pregnancy; Renal Dialysis; Renal Insufficiency

Topics: Acute Kidney Injury; Anemia; Epoetin Alfa; Erythropoietin; Humans; Renal Insufficiency