leptin and Anemia

Chronic kidney disease (CKD) patients have an extremely high risk of developing cardiovascular diseases (CVD) compared to the general population. Systemic inflammation associated with oxidative stress could be an important determinant of morbidity and mortality associated with CVD. We suspected that dysregulation of iron metabolism should be considered in these patients. Anemia is prevalent in CKD patients and is often treated with erythropoiesis-stimulating agents (ESAs) and iron. In addition, iron administration sometimes causes iron overdose. Excessive iron in the cytosol and mitochondria can accelerate the formation of a highly toxic reactive oxygen species, hydroxyl radicals, which damage lipids, proteins, and DNA. In this review, we propose the following four major reasons for oxidative stress in CKD patients: 1) iron is sequestered in cells by proinflammatory cytokines and hepcidin; 2) the reduction in frataxin increases "free" iron in mitochondria; 3) the accumulation of 5-aminolevulinic acid, a heme precursor, has toxic effects on iron and mitochondrial metabolism; and 4) the elevated levels of the metabolic hormone, leptin, promote hepatic hepcidin production. Although an efficient therapy for preventing oxidative stress in these patients has not yet been well defined, we propose that ESAs for renal anemia may ameliorate these causes of oxidative stress. Further clinical trials are necessary to clarify the effectiveness of ESAs on oxidative stress in CKD patients.

Topics: Aminolevulinic Acid; Anemia; Hematinics; Heme; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Leptin; Mitochondria; Oxidative Stress; Renal Insufficiency, Chronic

Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD.

Topics: Anemia; Bone and Bones; Bone Diseases, Metabolic; Dyslipidemias; Hematopoiesis; Humans; Leptin; Malnutrition; Nutritional Status; Receptors, Leptin; Renal Insufficiency, Chronic

An increasing number of studies emphasize the role of inflammation and metabolic changes in the induction of cancer-related symptoms, which can affect cancer evolution and prognosis. These changes result from the interactions between the tumor and the host. To date, however, markers of this peculiar condition, which can help clinicians to manage patients better, have still not been identified with certainty. Epithelial ovarian cancer (EOC) appears to be particularly appropriate to study these interactions because of its biological characteristics, its peculiar evolution, and the relevant scientific evidence available. Immunosuppression, anemia, depression, and weight loss affect the evolution of EOC and appear to be directly related to the immune-metabolic changes. In light of the aforementioned evidence, our review will focus on interleukin-6 (IL-6) and its role as potential marker of the patients' immune-metabolic status, to better monitor disease outcome and identify the most appropriate therapeutic strategy in EOC. Furthermore, leptin will be discussed as a sensor of the changes of energy metabolism induced by IL-6.

Topics: Anemia; Biomarkers; Carcinoma, Ovarian Epithelial; Endocrine System; Energy Metabolism; Female; Humans; Immune System; Interleukin-6; Leptin; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis

Therapeutic proteins have revolutionized the treatment of many diseases but low activity or rapid clearance limits their utility. New approaches have been taken to design drugs with enhanced in vivo activity and half-life to reduce injection frequency, increase convenience, and improve patient compliance. One recently used approach is glycoengineering, changing protein-associated carbohydrate to alter pharmacokinetic properties of proteins. This technology has been applied to erythropoietin and resulted in the discovery of darbepoetin alfa (DA), a hyperglycosylated analogue of erythropoietin that contains two additional N-linked carbohydrates, a threefold increase in serum half-life and increased in vivo activity compared to recombinant human erythropoietin (rHuEPO). The increased serum half-life allows for less frequent dosing to maintain target hemoglobin levels in anemic patients. Carbohydrates on DA and other molecules can also increase molecular stability, solubility, increase in vivo biological activity, and reduce immunogenicity. These properties are discussed.

Topics: Anemia; Animals; Antibody Formation; Darbepoetin alfa; Erythropoietin; Glycoproteins; Glycosylation; Humans; Leptin; Protein Engineering; Recombinant Proteins

Leptin is an adipokine that regulates various metabolism, but its association with secondary hyperparathyroidism (SHPT), a clinical manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD), remains obscure. Parathyroidectomy (PTX) is recommended for severe SHPT patients. Here, the associations between circulating leptin and clinical characteristics in CKD patients were investigated. Effects of PTX on leptin production were analyzed in vivo and in vitro. Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with body mass index (BMI) <23 kg/m(2). Serum leptin was related to anemia, albumin, and bone metabolism disorders in CKD patients. Lower intact parathyroid hormone (PTH) was related with higher leptin in PTX patients group. Severe SHPT inhibited uremia-enhanced leptin production in 3T3-L1 adipocytes, which was attenuated after PTX. High levels of PTH were found to reduce Akt phosphorylation and leptin production in vitro but high levels of calcium and phosphorus were not. Successful PTX was found to improve anemia and malnutrition in severe SHPT patients, and this was correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes. These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD.

Topics: Adolescent; Adult; Aged; Anemia; Bone Diseases; Female; Humans; Leptin; Male; Malnutrition; Middle Aged; Parathyroidectomy; Renal Insufficiency, Chronic

Dialysis patients with a high body mass index are less likely to experience severe anemia. Leptin, a hormone secreted by adipocytes, may have a role in protecting against renal anemia. The aim of the present study is to determine the effect of an increase in serum leptin levels by increasing energy intake on recombinant human erythropoietin (rHuEPO) response in long-term hemodialysis (HD) patients.. We enrolled 65 long-term HD patients to explore the association between leptin level and rHuEPO response by classifying them as either high- or low-leptin individuals (phase 1). Thereafter, 39 patients with malnutrition by means of Subjective Global Assessment were randomly assigned to high-energy and high-protein (an extra 475 kcal and 16.6 g of protein daily; group A; n = 12) or standard-energy, but high-protein (an extra 67.2 kcal and 16.8 g of protein daily; group B; n = 27), supplementation for 12 weeks. Serial serum leptin levels, nutritional measures, and hematologic parameters were obtained. Age- and sex-matched well-nourished patients (group C; n = 16) not administered extra nutritional supplementation served as control subjects (phase 2).. In phase 1, a significantly lower erythropoietin dose, greater hematocrit, and better nutritional measures were observed in the high-leptin group (P < 0.001). In phase 2, there was a significant increase in body fat mass (P = 0.001) and median serum leptin levels (P < 0.001) in response to 12 weeks of high-energy supplementation in group A, accompanied by markedly improved erythropoiesis (P < 0.05) compared with groups B and C.. Hyperleptinemia reflects better nutritional status and rHuEPO response in long-term HD patients. Increasing energy intake improves erythropoiesis, which may be mediated in part by an increase in serum leptin levels.

Topics: Adipose Tissue; Aged; Anemia; Body Composition; Cross-Sectional Studies; Dietary Proteins; Dietary Supplements; Drug Resistance; Energy Intake; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Prospective Studies; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis; Treatment Outcome

There are many growth factors (GFs), which stimulate the proliferation and maturation of erythroid progenitors. The main one is erythropoietin (Epo). Epo acts in concert with other GFs. Recently it was suggested that leptin (Lep) could be involved in a very early stage of erythropoiesis (E). The aim of this study was to analyse the relations between ability of idiopathic compensation of anemia by hemodialysis patients (HD pts) and concentration of Lep in HD men and women separately. The study was performed in 25/13M, 12F/HD pts, who idiopathically compensate anemia (group 1) and 29/16M, 13F/HD pts who required rHuEpo therapy (group 2). The mean Lep level in all women together was significantly higher than in all HD men together (26.9 +/- 6.3 ng/mL vs 6.8 +/- 0.9 ng/mL) but BMI was similar in men and women. We did not find significant differences in level of Lep in both studied groups of HD pts. Perhaps the lower influence of Epo and testosterone on E in HD women is compensated by significantly higher Lep concentration.

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Idiopathic non-clonal cytopenia (ICUS) and clonal cytopenia (CCUS) are common in the elderly population. While these entities have similar clinical presentations with peripheral blood cytopenia and less than 10% bone marrow dysplasia, their malignant potential is different and the biological relationship between these disorders and myeloid neoplasms such as myelodysplastic syndrome (MDS) is not fully understood. Aberrant DNA methylation has previously been described to play a vital role in MDS and acute myeloid leukemia (AML) pathogenesis. In addition, obesity confers a poorer prognosis in MDS with inferior overall survival and a higher rate of AML transformation. In this study, we measured DNA methylation of the promoter for the obesity-regulated gene LEP, encoding leptin, in hematopoietic cells from ICUS, CCUS and MDS patients and healthy controls. We investigated whether LEP promoter methylation is an early event in the development of myeloid neoplasms and whether it is associated with clinical outcome.. We found that blood cells of patients with ICUS, CCUS and MDS all have a significantly hypermethylated LEP promoter compared to healthy controls and that LEP hypermethylation is associated with anemia, increased bone marrow blast percentage, and lower plasma leptin levels. MDS patients with a high LEP promoter methylation have a higher risk of progression, shorter progression-free survival, and inferior overall survival. Furthermore, LEP promoter methylation was an independent risk factor for the progression of MDS in a multivariate Cox regression analysis.. In conclusion, hypermethylation of the LEP promoter is an early and frequent event in myeloid neoplasms and is associated with a worse prognosis.

Topics: Aged; Anemia; Clonal Hematopoiesis; DNA Methylation; Humans; Leptin; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Obesity

Hemodialyzed patients with poor erythropoietin response tend to have low volume of visceral adipose tissue and score high on malnutrition-inflammation score. This study investigates in-depth the role of leptin and chosen cytokines in the development of malnutrition-inflammation syndrome (MIS) and erythropoietin resistance.. Eighty-one hemodialyzed patients with erythropoietin-treated anemia were enrolled in the study. Their body composition was measured. Erythropoietin resistance index was calculated. Blood samples for leptin, IL-6, IL-18, TNF-alpha, and IL-1-alpha serum levels were drawn.. Leptin showed negative correlation with erythropoietin resistance index (ERI), whilst IL-6 showed the opposite. IL-6 seemed to be linked more to HD parameters and vintage, while TNF-alpha and leptin were more dependent on body composition. IL-18 and IL-1-alpha did not affect nutritional parameters nor ERI.. Modulation of adipokine- and cytokine-related signaling is a promising target in tempering malnutrition in hemodialyzed, and thus achieving better outcomes in anemia treatment. Large clinical studies that target the inflammatory response in hemodialysis, especially regarding IL-6, TNF-alpha, and leptin, would be of great worth.

Topics: Anemia; Erythropoietin; Humans; Inflammation; Interleukin-1; Interleukin-18; Interleukin-6; Kidney Failure, Chronic; Leptin; Malnutrition; Renal Dialysis; Tumor Necrosis Factor-alpha

Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men.. The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (MrOS) cohort (n = 1010; median age 75.3 years, range 69-81).. We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin (EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status].. In these elderly men, age was negatively associated with Hb (r = -0.12, P < 0.001) and positively associated with adiponectin level (r = 0.13, P < 0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated (r = -0.20, P < 0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130 g L(-1) ) compared to nonanaemic men (14.0 vs. 11.7 μg mL(-1) , P < 0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes.. Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men.

Topics: Adiponectin; Aged; Aged, 80 and over; Aging; Anemia; Body Composition; Erythropoietin; Estradiol; Ferritins; Gonadal Steroid Hormones; Hemoglobins; Humans; Insulin; Leptin; Male; Multivariate Analysis; Thiamine

To study factors associated with anemia and its effect on survival in HIV-infected persons treated with modern combined antiretroviral therapy (cART), we characterized the prevalence of anemia in the Veterans Aging Cohort Study (VACS) and used a candidate gene approach to identify proinflammatory gene single nucleotide polymorphisms (SNPs) associated with anemia in HIV disease. The study comprised 1597 HIV(+) and 865 HIV(-) VACS subjects with DNA, blood, and annotated clinical data available for analysis. Anemia was defined according to World Health Organization criteria (hemoglobin < 13 g/dL and < 12 g/dL in men and women, respectively). The prevalence of anemia in HIV(+) and HIV(-) subjects was 23.1% and 12.9%, respectively. Independent of HIV status, anemia was present in 23.4% and 8% in blacks and whites, respectively. Analysis of our candidate genes revealed that the leptin -2548 G/A SNP was associated with anemia in HIV(+), but not HIV(-), patients, with the AA and AG genotypes significantly predicting anemia (P < .003 and P < .039, respectively, logistic regression). This association was replicated in an independent cohort of HIV(+) women. Our study provides novel insight into the association between genetic variability in the leptin gene and anemia in HIV(+) individuals.

Topics: Adult; Aged; Anemia; Anti-Retroviral Agents; Cohort Studies; Female; Genetic Predisposition to Disease; Genetic Variation; Hemoglobins; HIV Infections; Humans; Leptin; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Promoter Regions, Genetic; Veterans

To evaluate the relationship between hyperleptinemia and anemia in hemodialysis patients, we investigated the reverse epidemiological role of leptin in 36 patients (males: 21, diabetics: 11) under regular chronic hemodialysis. The patients had complete blood counts, iron profile, serum leptin, and adequacy of hemodialysis measured. We found a significant positive correlation of serum leptin with hemoglobin level and body mass index (BMI). A trend between serum leptin and total iron binding capacity was observed, however, no correlation was observed with serum ferritin. No differences in these correlations were observed in any subgroup related to gender or diabetes. Our data support previous findings showing that greater serum leptin levels are associated with greater hemoglobin levels.

Topics: Adult; Anemia; Cross-Sectional Studies; Diabetic Nephropathies; Female; Ferritins; Hemoglobins; Humans; Leptin; Male; Middle Aged; Renal Dialysis

Anemia occurs in more than 30% of patients with epithelial ovarian cancer before any surgery. High levels of proinflammatory cytokines and increased oxidative stress may contribute to the development of cancer-related anemia. We assessed a population of previously untreated patients with advanced epithelial ovarian cancer to evaluate whether there was a correlation between hemoglobin (Hb) and parameters of inflammation and oxidative stress, stage of disease, and performance status (PS). In 91 patients with epithelial ovarian cancer and 95 healthy women matched for age, weight, and height, levels of Hb, C-reactive protein (CRP), fibrinogen (Fbg), proinflammatory cytokines, leptin, reactive oxygen species (ROS), and antioxidant enzymes were assessed at diagnosis before treatment. The correlations between Hb, parameters of inflammation and oxidative stress, stage, and PS were evaluated. Hb levels were lower in patients with advanced epithelial ovarian cancer than in control subjects and inversely related to stage and PS. Hb negatively correlated with CRP, Fbg, interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), and ROS, and positively correlated with leptin and glutathione peroxidase (GPx). Multivariate regression analysis showed that stage and IL-6 were independent factors determining Hb values. This evidence suggests that anemia in epithelial ovarian cancer is common and its presence is related to stage of disease and markers of inflammation.

Topics: Aged; Aged, 80 and over; Anemia; Biomarkers; C-Reactive Protein; Epithelial Cells; Erythrocyte Count; Female; Ferritins; Fibrinogen; Glutathione Peroxidase; Hemoglobins; Humans; Interleukin-1; Interleukin-6; Iron; Leptin; Middle Aged; Ovarian Neoplasms; Reactive Oxygen Species; Reticulocyte Count; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Dose requirements of epoetin vary considerably among patients with end-stage renal disease (ESRD), whereas determinants of epoetin sensitivity are poorly understood. Fat mass is an important source of adipokines, including interleukin 6 (IL-6), which is associated with decreased epoetin sensitivity. Furthermore, the adipokine leptin stimulates human erythroid development in vitro. In the present study, we investigate the impact of fat mass and leptin level on epoetin sensitivity in patients with ESRD.. One hundred sixty-six patients with ESRD (107 men; 64%) with a mean age of 56.9 +/- 0.9 years were studied in a post hoc cross-sectional analysis. Body composition was analyzed by dual-energy X-ray absorptiometry and correlated with serum markers of inflammation and leptin (analyzed by enzyme-linked immunosorbent assays), as well as with epoetin dose, in international units administered per week (IU/wk). To correct for differences in body mass and hemoglobin (Hb) levels, epoetin sensitivity was approximated as epoetin/Hb ratio, ie, epoetin dose per unit of Hb (IU/wk/g/dL) and epoetin/Hb/kg ratio, ie, epoetin dose per unit of Hb and kilogram of patient body weight (IU/wk/Hb/kg).. Patients were divided into 3 groups according to epoetin/Hb/kg ratio (no-epoetin group, low-epoetin group, and high-epoetin group). The 3 groups had significantly different serum levels of high-sensitivity C-reactive protein (hsCRP; median, 8.6 versus 3.1 and 8.0 mg/L, respectively; P < 0.05), neopterin (median, 112.4 versus 94.3 and 96.1 ng/L, respectively; P < 0.05), and IL-6 (median, 6.8 versus 4.1 and 6.5 ng/mL, respectively; P < 0.05). Significant between-group differences also were found in fat mass and leptin levels (median, 14.8 versus 10.5 and 7.9 ng/mL, respectively; P = 0.02). In univariate analyses, significant relationships between epoetin sensitivity indices, leptin levels, and levels of the inflammatory markers hsCRP and IL-6 were found. In a multivariate stepwise regression model, log ferritin, parathyroid hormone, log leptin, log IL-6, and polycystic kidney disease were significantly associated with the epoetin/Hb ratio.. The present study shows that leptin level may be a predictor of epoetin sensitivity. The effect could be either direct stimulation of erythropoiesis or indirect stimulation by associated adipokines. Although truncal fat is associated with secretion of proinflammatory cytokines, this secretion appears not to have inhibitory effects on epoetin sensitivity in the presence of high leptin levels.

Topics: Adipose Tissue; Anemia; Body Composition; C-Reactive Protein; Cross-Sectional Studies; Darbepoetin alfa; Drug Resistance; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Organ Size; Polycystic Kidney Diseases; Renal Dialysis; Sweden

Delivery of protein therapeutics often requires frequent injections because of low activity or rapid clearance, thereby placing a burden on patients and caregivers. Using glycoengineering, we have increased and prolonged the activity of proteins, thus allowing reduced frequency of administration. Glycosylation analogs with new N-linked glycosylation consensus sequences introduced into the protein were screened for the presence of additional N-linked carbohydrates and retention of in vitro activity. Suitable consensus sequences were combined in one molecule, resulting in glycosylation analogs of rHuEPO, leptin, and Mpl ligand. All three molecules had substantially increased in vivo activity and prolonged duration of action. Because these proteins were of three different classes (rHuEPO is an N-linked glycoprotein, Mpl ligand an O-linked glycoprotein, and leptin contains no carbohydrate), glycoengineering may be generally applicable as a strategy for increasing the in vivo activity and duration of action of proteins. This strategy has been validated clinically for glycoengineered rHuEPO (darbopoetin alfa).

Topics: Anemia; Animals; CHO Cells; COS Cells; Cricetinae; Drug Delivery Systems; Erythropoietin; Excipients; Female; Genetic Enhancement; Glycoproteins; Humans; Leptin; Mice; Mice, Inbred BALB C; Protein Engineering; Proteins; Recombinant Proteins; Thrombopoietin

Hyperleptinemia is also common in chronic renal failure, particularly in CAPD. On the other hand, cardiovascular events related to thrombosis are a predominant cause of death and account also for an important morbidity in uremic patients. Treatment with recombinant human erythropoietin (rHuEPO) may shift the precarious hemostatic balance towards thrombosis. Therefore, the aim of the study was to assess the relationships between leptin and platelet aggregation and some hemostatic parameters in CAPD patients treated with rHuEPO. The study was performed on 15 patients maintained on CAPD given rHuEPO and 13 subjects without rHuEPO therapy served as a control group. Platelet aggregation was studied in both platelet-rich plasma (PRP) and in the whole blood. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) (antigens and activities), von Willebrand factor, trombomodulin, protein C, thrombin activatable fibrinolysis inhibitor (TAFI) and leptin (serum and dialysate) were assayed by using commercially available kits. Patients in both groups studied did not differ significantly with respect to age, BMI, duration of renal replacement therapy, and other hematological and hemostatic parameters studied as well as leptin serum and dialysate leptin. In CAPD patients treated with rHuEPO serum and dialysate leptin significantly correlated with tissue factor pathway inhibitor, protein C, thrombomodulin, ristocetin-induced platelet aggregation in the whole blood and PRP. In CAPD patients not treated with rHuEPO the significant correlations were observed between serum and dialysate leptin and protein C. Positive correlations between platelet aggregation and leptinemia in CAPD patients might indicate that hyperleptinemia could be associated with the cardiovascular disease in dialyzed patients. Leptin might contribute at least in part to the thrombotic complications observed in CAPD patients.

Topics: Adult; Anemia; Erythropoietin; Female; Hemostasis; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Platelet Aggregation; Recombinant Proteins