leptin and Uremia

The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients.

Topics: Adipokines; Adiponectin; Adipose Tissue; Drug-Related Side Effects and Adverse Reactions; Humans; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Oxidative Stress; Resistin; Signal Transduction; Uremia

Adipose tissue is no longer considered to be an inert tissue of which function is to store fat. It actively secretes a number of biologic active compounds that are involved in the regulation of many processes like food intake, energy expenditure, metabolism homeostasis, immunity and blood pressure homeostasis. General metabolism alteration in patients with chronic kidney disease has a profound impact on biology of adipocytes. Chronic renal failure is a pathological condition, of which two major hallmarks are chronic inflammation and insulin resistance. In uraemic patients, adipose tissue became an important source of molecules that are responsible, at least in part, for the metabolic disturbances seen in these patients. Some of these molecules act as pro-inflammatory agents contributing to the maintenance and enhancement of the chronic inflammatory response. These pro-inflammatory molecules, along with other molecules secreted by the adipose tissue, have a central position in the aetiology of uraemia-associated insulin resistance. In this review, we intend to summarize some aspects of the biology of adipokines in uraemia, with emphasis on the link between these molecules and insulin resistance.

Topics: Adiponectin; Adipose Tissue; Humans; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Resistin; Uremia

Patients with chronic kidney disease frequently experience loss of appetite (anorexia), which increases in severity during the progression of the disease and may lead to protein-energy wasting, morbidity, and mortality. Anorexia represents a multiple, complex, and multifactorial disorder that may have its origin in renal failure (contemplating not only retention of uremic toxins but also peptides and cytokines) but that later on also involves metabolic abnormalities not yet corrected by dialysis therapy. This paper reviews current knowledge about the clinical signs of uremic anorexia as well as mechanisms involved. Based on megestrol acetate interventions and the recent observation that sex may modulate uremic appetite behavior, the potential role of sex hormones in treating chronic kidney disease anorexia needs to be further explored.

Topics: Anorexia; Appetite; Cytokines; Feeding and Eating Disorders; Homeostasis; Humans; Intestinal Absorption; Leptin; Nitric Oxide; Uremia

This article reviews current knowledge about mechanisms responsible for uremic events, especially those that involve the central nervous system (CNS). Anorexia is a frequent complication of the uremic syndrome that contributes to malnutrition in patients on dialysis. Uremic anorexia has been associated with many factors. Traditionally, anorexia in dialysis patients has been regarded as a sign of uremic toxicity; therefore, 2 hypotheses have been proposed: the "middle molecule" and "peak concentration" hypotheses; both of these remain unproved. Recently, our group has proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino acid profile that may be acquired when the patient is in uremic status. It is characterized by low concentrations of large neutral and branched chain amino acids in the cerebrospinal fluid. This situation permits a high level of tryptophan transport across the blood-brain barrier and enhances the synthesis of serotonin (the final target responsible for inhibiting appetite). The role of inflammation in the genesis of anorexia-malnutrition is also emphasized. In summary, in the CNS, factors associated with uremic anorexia include high levels within the cerebrospinal fluid of proinflammatory cytokines, leptin, and free tryptophan and serotonin (hyperserotoninergic-like syndrome), along with deficiency of neural nitric oxide (nNO) and disorders in various receptors such as melanocortin receptor-4 (MC4-R). Uremic anorexia is a complex complication associated with malnutrition and high levels of morbidity and mortality. Several uremia-acquired disorders in the CNS such as high cerebrospinal fluid levels of anorexigen substances and disorders in appetite regulator receptors may explain the lack of appetite.

Topics: Amino Acids; Anorexia; Appetite Regulation; Brain; Cytokines; Humans; Leptin; Nitric Oxide; Serotonin; Uremia

Enhanced chronic systemic inflammation and reduced insulin sensitivity are often associated in patients with chronic renal failure, contributing to cardiovascular morbidity and mortality in these patients. Adipose tissue produces several hormones (adipocytokines including leptin, resistin, tumor necrosis factor-alpha, and adiponectin) that modulate both systemic inflammatory response and insulin action. High leptin, resistin, and tumor necrosis factor-alpha and low adiponectin are associated with proinflammatory conditions, whereas opposite patterns are commonly observed in the presence of increased insulin sensitivity, low inflammation, and reduced cardiovascular risk. Oxidative stress has also been shown recently to modulate adipocytokine production, resulting in a proinflammatory profile. Increments of plasma concentrations of both proinflammatory and anti-inflammatory adipocytokines have been reported in chronic renal failure, possibly caused by both passive accumulation from reduced renal excretion and metabolic abnormalities induced by uremia. The potential role of altered adipose tissue adipocytokine production in the onset of renal failure-associated inflammatory and metabolic derangements remains largely to be elucidated and is discussed in the current report.

Topics: Adiponectin; Adipose Tissue; Cytokines; Ghrelin; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Leptin; Nutritional Physiological Phenomena; Oxidative Stress; Peptide Hormones; Uremia

The hypothesis that alterations of serum concentrations of the anorexigenic adipose tissue-derived hormone leptin or the orexigenic peptide ghrelin might help to regain appetite and fight malnutrition in patients with chronic renal failure cannot be confirmed at present. For the future, however, strategies interfering with signal transduction of these peptides in the hypothalamus might be more promising and should be investigated and further developed.

Topics: Appetite; Disease Progression; Ghrelin; Humans; Kidney Diseases; Kidney Failure, Chronic; Leptin; Osmolar Concentration; Peptide Hormones; Uremia

Topics: Animals; Biomarkers; Cachexia; Disease Progression; Humans; Leptin; Uremia

Topics: Animals; Appetite; Biological Transport, Active; Blood-Brain Barrier; Carrier Proteins; Central Nervous System; Cytokines; Female; Gene Expression Regulation; Glucocorticoids; Humans; Insulin; Kidney Diseases; Leptin; Male; Mice; Obesity; Proteins; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Uremia

Inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia but why uremia up-regulates pro-inflammatory cytokines is unknown. Toll-like receptors (TLRs) regulate locally the innate immune responses, but it is unknown whether in chronic kidney disease (CKD) TLR4 muscle signalling is altered. The aim of the study is to investigate whether in CKD muscle, TLRs had abnormal function and may be involved in transcription of pro-inflammatory cytokine.. TLR4, phospho-p65, phospho-ikBα, tumour necrosis factor (TNF)-α, phospho p38, Murf 1, and atrogin were studied in skeletal muscle from nondiabetic CKD stage 5 patients (n = 29) and controls (n = 14) by immunohistochemistry, western blot, and RT-PCR. Muscle cell cultures (C2C12) exposed to uremic serum were employed to study TLR4 expression (western blot and RT-PCR) and TLR-driven signalling. TLR4 signalling was abrogated by a small molecule chemical inhibitor or TLR4 siRNA. Phospho AKT and phospho p38 were evaluated by western blot.. CKD subjects had elevated TLR4 gene and protein expression. Also expression of NFkB, p38 MAPK and the NFkB-regulated gene TNF-α was increased. At multivariate analysis, TLR4 protein content was predicted by eGFR and Subjective Global Assessment, suggesting that the progressive decline in renal function and wasting mediate TLR4 activation. In C2C12, uremic serum increased TLR4 as well as TNF-α and down-regulated pAkt. These effects were prevented by blockade of TLR4.. CKD promotes muscle inflammation through an up-regulation of TLR4, which may activate downward inflammatory signals such as TNF-α and NFkB-regulated genes.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Animals; C-Reactive Protein; Cell Line; Cytokines; Female; Humans; Inflammation; Leptin; Male; Mice; Middle Aged; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Rectus Abdominis; Renal Insufficiency, Chronic; Resistin; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Uremia

Topics: Body Mass Index; Female; Humans; Inflammation Mediators; Leptin; Male; Uremia

To explore the relation between high leptin and inflammation in uremic patients.. A group of 73 uremic patients in dialysis center of our Department were assigned as uremic group; a group of 30 healthy persons who were examined over the same period were regarded as control group. The level of body mass index (BMI), serum creatinine (SCr), blood urea nitrogen (BUN), leptin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10, and the neutrophils phagocytosis function were compared in two groups.. BMI and IL-10 of uremic group were lower than the control group. The levels of SCr, BUN, leptin, TNF-α, IL-6 of uremic group were higher than the control group (p < 0.05). The neutrophils phagocytosis function in uremic group significantly decreases, compared to control group (p < 0.05). Using one-way ANOVA analysis, serum leptin was positively correlated with the level of TNF-α, IL-6 (r = 0.58, 1.00 respectively, p < 0.05), and was negatively correlated with the level of IL-10 (r = -0.45, p < 0.05).. The high level of leptin and correlated inflammation were involved in the initiation and development of uremia; moreover, leptin was an important mediator.

Topics: Adult; Aged; Body Mass Index; Female; Humans; Inflammation; Inflammation Mediators; Leptin; Male; Middle Aged; Neutrophils; Phagocytosis; Urea; Uremia; Young Adult

Recognition of adipose-related signaling in surgery is increasing, although direct interrogation of human adipose has been sparse. Few scenarios rival uremia for health impact. We hypothesized that adipose from uremic patients holds a relatively higher adipose-derived hormone and proinflammatory adipokine signature; we simultaneously evaluated the impact of clinical parameters on adipose phenotype.. Adipose was harvested from surgical patients. Histology and protein analyses were completed for select mediators.. In the overall cohort of 71 patients, the mean age was 63.4 y; 46.4% of patients had diabetes mellitus, 49.2% had hyperlipidemia, and 53.5% had coronary artery disease. Compared with nonuremic patients, uremic patients had one-tenth of the levels of leptin (P < 0.001), one-third of the levels of adiponectin (P < 0.001), and threefold higher levels of resistin (P < 0.001). Females had sixfold higher levels of leptin, 1.5-fold higher levels of adiponectin, and twofold higher levels of tumor necrosis factor alpha but equivalent resistin. There were differences in mediators when stratified by age. In both the obese and nonobese strata, we observed a concordant pattern of association (magnitude or significance) of uremia and leptin, adiponectin, and resistin. No differentials in other mediators emerged on body mass index stratification. Multiple regression analysis for leptin, adiponectin, and resistin (with age, gender, and uremia as independent variables) showed uremia as the highest independent predictor of all the three mediators.. Advanced chronic kidney disease is associated with perturbations in adipose-derived hormones (leptin, adiponectin, and resistin). Adipose adiponectin and leptin (in contrast to reported plasma levels) were lower in uremic patients; there is an inverse correlation between adipose resistin and renal function. Compared with other clinical parameters including body mass index, uremia dominates overall in determining adipose phenotype, highlighting the complex biological interplay between uremia and adipose biology.

Topics: Adiponectin; Aged; Aged, 80 and over; Cohort Studies; Female; Humans; Kidney; Leptin; Male; Middle Aged; Phenotype; Prospective Studies; Renal Insufficiency, Chronic; Resistin; Subcutaneous Fat; Uremia

Chronic kidney disease (CKD) is frequently associated with malnutrition, anorexia, and hyperleptinemia. This study was designed to test the hypothesis that a component of the uremic milieu may trigger leptin release by adipocytes. To this end, mouse 3T3-L1 adipocytes were incubated for 16 hours in culture medium containing urea (80 mM) or plasma from either healthy volunteers or patients with CKD (20%, v/v). Uremic plasma and not urea induced a large release of leptin (+557%, P < .01). These results suggest that the hyperleptinemia reported in patients with CKD, could be, at least in part, because of an overproduction of leptin by the adipose tissue.

Topics: 3T3-L1 Cells; Adipocytes; Analysis of Variance; Animals; Cells, Cultured; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Mice; Middle Aged; Urea; Uremia

Anorexia is a common complication of chronic kidney disease (CKD), while novel animal and human data suggest a role for visfatin in regulating feeding behavior. We hypothesized that increased visfatin levels in CKD patients may be involved in the regulation of appetite and nutrient homeostasis.. This is a cross-sectional study where circulating visfatin levels were analysed in 246 incident CKD stage 5 patients starting dialysis therapy. The associations between visfatin (enzyme-linked immunosorbent assay, ELISA) and anthropometric and biochemical nutritional status, self-reported appetite, fasting serum amino acids (high-performance liquid chromatography) and circulating cytokine levels (ELISAs) were assessed. We also performed genotyping (Pyrosequencing(R)) of two polymorphisms (rs1319501 and rs9770242) in the visfatin gene.. Serum visfatin concentrations were not associated with either body mass index or serum leptin. Across groups with worsening appetite, median visfatin levels were incrementally higher (P < 0.05). With increasing visfatin tertiles, patients proved to be more often anorectic (P < 0.05) and to have incrementally lower serum albumin, cholesterol and triglycerides as well as lower essential and non-essential serum amino acids (P < 0.05 for all). A polymorphism in the visfatin gene was associated with increased circulating visfatin levels and, at the same time, a higher prevalence of poor appetite (P < 0.05 for both).. Our study suggests novel links between visfatin and anorexia in CKD patients. Based on recent studies, we speculate that high visfatin in CKD patients may constitute a counter-regulatory response to central visfatin resistance in uremia. Future studies should examine a putative role of visfatin as a regulator of nutrient homeostasis in uremia.

Topics: Adult; Aged; Amino Acids; Appetite; Body Mass Index; Chronic Disease; Cross-Sectional Studies; Feeding Behavior; Female; Homeostasis; Humans; Kidney Diseases; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Polymorphism, Genetic; Triglycerides; Uremia

End-stage renal disease (ESRD) is commonly associated with anorexia, malnutrition and inflammation. In addition to serving as the primary reservoir for energy storage, adipocytes produce numerous pro- and anti-inflammatory mediators and regulate food intake by releasing the appetite-suppressing (leptin) and appetite-stimulating (adiponectin) hormones. Under normal conditions, release of leptin is stimulated by feeding to prevent excess intake, and release of adiponectin is stimulated by fasting to induce feeding. However, under certain pathological conditions such as inflammation, maladaptive release of these hormones leads to anorexia, wasting and malnutrition and simultaneously intensifies inflammation. Anorexia, malnutrition and inflammation in ESRD are frequently accompanied by hyper-leptinaemia. This study was designed to test the hypothesis that uraemic plasma may stimulate leptin release and suppress adiponectin release in normal adipocytes.. Visceral adipose tissue was harvested from normal rats, and adipocytes were isolated and incubated for 2-4 h in media containing 90% plasma from 12 ESRD patients (before and after haemodialysis) and 12 normal control subjects.. The ESRD group had a marked elevation of plasma TNF-alpha, IL-6, IL-8 and leptin concentrations before and after haemodialysis. Incubation in media containing plasma from the ESRD group elicited a much greater leptin release by adipocytes than that containing normal plasma. Post-dialysis plasma evoked an equally intense leptin release. The rise in leptin release was coupled with a parallel fall in TNF-alpha concentration in the incubation media. In contrast to leptin, adiponectin release in the presence of uraemic plasma was similar to that found with the control plasma.. Exposure to uraemic plasma induces exuberant release of leptin that is coupled with avid uptake of TNF-alpha by visceral adipocytes. These observations confirm the role of TNF-alpha, formerly known as cachexin, in the over-production and release of leptin in patients with ESRD.

Topics: Adipocytes; Adult; Animals; Cells, Cultured; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Plasma; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Uremia

Muscle wasting is a hallmark of uremic cachexia and has frequently been attributed to malnutrition that manifests as anorexia in chronic kidney disease. However, recent evidence indicates that proteolytic mechanisms are responsible for atrophy. Cheung and colleagues have reexamined the links between loss of lean body mass and nutrition. They demonstrate that neuropeptide signaling pathways, which regulate appetite and energy expenditure, also affect expression of key proteins involved in muscle mass maintenance.

Topics: Animals; Appetite Regulation; Cachexia; Chronic Disease; Humans; Leptin; Male; Melanocortins; Mice; Muscle, Skeletal; Muscular Atrophy; Nutritional Requirements; Signal Transduction; Uremia

Insulin-like growth factor (IGF)-I increases muscle mass while myostatin inhibits its development. Muscle wasting is common in patients with uremic cachexia and may be due to imbalance of this regulation. We had proposed a central mechanism involving leptin and melanocortin signaling in the pathogenesis of uremic cachexia since agouti-related peptide (AgRP), a melanocortin-4 receptor antagonist, reduced uremic cachexia. Here we found that injection of AgRP into the cerebral ventricles resulted in a gain of body mass and improved metabolic rate regulation in a mouse model of uremic cachexia. These salutary effects occurred independent of increased protein and calorie intake. Myostatin mRNA and protein concentrations were increased while those of IGF-I were decreased in the skeletal muscle of uremic mice. AgRP treatment partially corrected these uremia-induced changes. Suppressor of cytokine signaling-2 gene expression (SOCS2) was significantly increased in uremic animals and AgRP reduced this expression. We suggest that AgRP improves uremic cachexia and muscle wasting by a peripheral mechanism involving the balance between myostatin and IGF-I.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Cachexia; Chronic Disease; Gene Expression; Humans; Insulin-Like Growth Factor I; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Muscular Atrophy; Myostatin; Nephrectomy; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transforming Growth Factor beta; Uremia

Topics: Biomarkers; Body Mass Index; Cachexia; Female; Humans; Leptin; Male; Renal Dialysis; Uremia

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Topics: Agouti-Related Protein; Animals; Body Weight; Cachexia; Eating; Gene Expression Regulation; Humans; Leptin; Mice; Mice, Knockout; Peptide Fragments; Proteasome Endopeptidase Complex; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Ubiquitin C; Uremia

Leptin is a pleiotropic molecule involved in energy homeostasis, hematopoiesis, inflammation, and immunity. Hypoleptinemia characterizing starvation has been strictly related to increased susceptibility to infection secondary to malnutrition. Nevertheless, ESRD is characterized by high susceptibility to bacterial infection despite hyperleptinemia. Defects in neutrophils play a crucial role in the infectious morbidity, and several uremic toxins that are capable of depressing neutrophil functions have been identified. Only a few and contrasting reports about leptin and neutrophils are available. This study provides evidence that leptin inhibits neutrophil migration in response to classical chemoattractants. Moreover, serum from patients with ESRD inhibits migration of normal neutrophils in response to N-formyl-methionyl-leucyl-phenylalanine with a strict correlation between serum leptin levels and serum ability to suppress neutrophil locomotion. Finally, the serum inhibitory activity can be effectively prevented by immune depletion of leptin. The results also show, however, that leptin by itself is endowed with chemotactic activity toward neutrophils. The two activities-inhibition of the cell response to chemokines and stimulation of neutrophil migration-could be detected at similar concentrations. On the contrary, neutrophils exposed to leptin did not display detectable [Ca(2+)](i) mobilization, oxidant production, or beta(2)-integrin upregulation. The results demonstrate that leptin is a pure chemoattractant devoid of secretagogue properties that are capable of inhibiting neutrophil chemotaxis to classical neutrophilic chemoattractants. Taking into account the crucial role of neutrophils in host defense, the leptin-mediated ability of ERSD serum to inhibit neutrophil chemotaxis appears as a potential mechanism that contributes to the establishment of infections in ERSD.

Topics: Chemotaxis, Leukocyte; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Neutrophils; Toxins, Biological; Uremia

Leptin has been shown to function as an inhibitor of appetite and energy expenditure accelerator. However, it was recently reported that leptin has other important functions as a fibrogenetic factor and a novel, independent risk factor for coronary heart disease. The present study aimed to assess the blood concentration of leptin in acute uraemic rats by using various peritoneal dialysis (PD) solutions.. To induce acute renal failure, the bilateral renal arteries were ligated via a mid-abdominal incision 1 h before starting PD. Rats were divided into four groups: 13.6 g/L glucose-containing dialysate (group L); 38.6 g/L glucose-containing dialysate (group H); 13.6 g/L glucose and 25 g/L mannitol-containing dialysate with equal osmotic pressure to the dialysate of group H (group M); and renal failure without PD (group F). The concentrations of glucose, urea nitrogen (UN), leptin and insulin were measured at 0, 2 and 4 h after starting PD.. We observed significant blood UN suppression in all dialysed groups. Blood glucose was significantly higher in rats treated with the high glucose solution than in those treated with the low glucose solution. Insulin and leptin significantly increased in the high glucose solution group. There was a strong correlation between the blood glucose and insulin levels. We also found a strong correlation between the percentage changes in blood glucose and leptin. The relationship between the percentage changes in insulin and leptin were weak but significant.. The high glucose PD solution resulted in increased circulating levels of leptin, glucose, and insulin, suggesting that these changes are linked with PD performed with glucose-based dialysis fluid.

Topics: Acute Kidney Injury; Animals; Glucose Solution, Hypertonic; Hemodialysis Solutions; Leptin; Male; Peritoneal Dialysis; Rats; Rats, Sprague-Dawley; Uremia

In chronic renal failure leptin levels are elevated and BMD decreased, however, so far data about correlations between leptin and BMD in dialyzed patients are scarce. It has been suggested that leptin is a predictor of BMD in postmenopausal women. We examined the relationships between leptinemia, BMD and bone metabolism in HD and CAPD patients. We also assessed whether leptin is significant and independent predictor of BMD in dialyzed patients.. BMD was measured using dual energy X-ray absorptiometry (DEXA) at lumbar spine and femoral neck in 25 HD and 23 CAPD patients. Markers of bone turnover and leptin were studied using commercially available kits.. In femoral neck BMD was significantly higher in CAPD patients, without significant differences in BMD in lumbar spine. There was a negative correlation between BMD at the femoral neck and time on hemodialysis (r= -0.45, p < 0.05). In CAPD patients BMD at the lumbar spine correlated negatively with vitamin D3 (r= -0.54, p < 0.05), osteocalcin (r= 0.54, p < 0 .05), and positively with BMI (r= 0.63, p < 0.01). BMD at the femoral neck correlated positively with BMI (r= 0.59, p < 0.01), and negatively with osteocalcin (r= -0.63, p < 0.05) and time on CAPD (r= -0.52, p < 0.05). Leptin correlate only with cholesterol (r= 0.25, p < 0.05), TSH (r= 0.35, p < 0.01), ss(2) microglobulin (r= 0.32, p < 0.001) and BMD at the femoral neck (r= -0.23, p < 0.05)in all dialyzed (HD and CAPD) patients.. BMD depends on time of renal replacement therapy. Biochemical markers of bone metabolism poorly correlate with BMD and leptin in dialyzed patients. Leptin is not a predictor of BMD in dialyzed patients.

Topics: Adult; Biomarkers; Bone and Bones; Bone Density; Cholecalciferol; Female; Humans; Leptin; Male; Middle Aged; Osteocalcin; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Uremia

Patients with chronic renal failure are characterized by hyperleptinemia, and leptin is presumed to be an anorectogenic hormone. The aim of this prospective study was to analyze changes in body composition and parameters of nutritional status in relation to changes in plasma leptin concentration in uremic patients during the first year of hemodialysis therapy.. 21 patients (10 F, 11 M, mean age 51+/- 3 years, BMI 24.3+/-1.1 kg/m2) were enrolled in this study. Nutritional status was evaluated by anthropometric parameters, estimation of body composition (DEXA method), and biochemical markers (plasma concentrations of albumin, cholesterol, triglycerides, transferrin) and plasma leptin concentration. Tests were performed twice: immediately after initiation of hemodialysis therapy and again 12 months later.. After 12 months of hemodialysis therapy, the changes in body mass (-2.6+/-0.8 kg; p=0.23), total fat mass (TFM) (-0.3+/-0.8 kg; p=0.68) and total lean mass (TLM) (+0.5+/-0.8 kg; p=0.26) were insignificant. Plasma leptin concentration and estimated biochemical nutritional parameters did not change markedly. A significant positive correlation was noticed between TFM and plasma leptin concentration (R=0.521; p=0.02) at the beginning of hemodialysis therapy and between changes in TFM and plasma leptin concentration (R=0.466; p=0.04) after one year.. Plasma leptin concentration does not predict forthcoming changes in body composition and changes of nutritional status in uremic patients after the first year of hemodialysis.

Topics: Body Composition; Body Mass Index; C-Reactive Protein; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Nutritional Status; Predictive Value of Tests; Renal Dialysis; Statistics as Topic; Uremia

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

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

To investigate the leptin levels of hemodialysis (HD) patients and the relation to their nutritional status.. Thirty maintenance hemodialysis patients and thirty healthy control subjects were recruited for the study. Blood was drawn after an overnight fast. Serum leptin was measured using a human leptin RIA kit. There were also blood tests to measure BUN, creatinine, serum albumin, transferrin, prealbumin, insulin, cholesterol etc.. Mean serum leptin concentration was significantly higher in the HD group than that in the control (P < 0.01). HD group had significantly higher concentrations of BUN, creatinine, serum albumin, transferrin and prealbumin (P < 0.01). Leptin levels in HD patients correlated positively with body mass index (BMI), total systemic flow (TSF), and concentration of insulin (r = 0.53, 0.66, 0.57, respectively, P < 0.01). No significant correlations were observed in HD patients between leptin and BUN or creatinine, or between leptin and nutritional indices.. Our data suggests that leptin is markedly increased in HD patients. Serum leptin correlates strongly with BMI, TSF and insulin level. No significant correlations were observed in HD patients between leptin and other indices.

Topics: Adult; Aged; Body Mass Index; Female; Humans; Leptin; Male; Middle Aged; Nutritional Status; Radioimmunoassay; Renal Dialysis; Uremia

Serum leptin levels are increased in chronic renal failure (CRF) and may potentially contribute to protein malnutrition in this disorder.. Following a cross-sectional design, we performed a nutritional survey in a wide sample of uremic patients treated conservatively (n = 87), with peritoneal dialysis (n = 71) and with hemodialysis (n = 53). Then, we analyzed the correlation between serum leptin levels and markers of protein malnutrition. We used a multivariate approach, taking into consideration the confounding effect of other factors on the correlation between hyperleptinemia and protein malnutrition.. Both univariate and multivariate analysis disclosed a poor correlation between hyperleptinemia and markers of protein malnutrition. In fact, there were trends to a positive correlation between leptinemia and body protein stores, as estimated from the scrutinized markers. Persistence of the basic correlation between general intake, fat mass and leptin in CRF could partially explain these findings, but neither a negative correlation between leptin levels nor protein nutritional state could be disclosed after controlling for this factor.. Our results do not support a first-line role for hyperleptinemia in the genesis of protein malnutrition of uremia.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Female; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Multivariate Analysis; Peritoneal Dialysis, Continuous Ambulatory; Prealbumin; Protein-Energy Malnutrition; Renal Dialysis; Serum Albumin; Transferrin; Uremia

This was the first Korean-Polish seminar on renal replacement therapies which provided a survey of current research being carried out in both countries, delivered by leading experts in this field. The topics included malnutrition in uremia, biocompatibility, risk factors and complications in renal replacement therapy, diabetic nephropathy, new solutions for peritoneal dialysis, and peritoneal transport. The organizers strove to select the topics which are currently of interest to researchers from both countries with the purpose to compare results and stimulate discussion concerning possible collaboration in the future.

Topics: Cardiovascular Diseases; Diabetic Nephropathies; Humans; Kidney Failure, Chronic; Leptin; Nutrition Disorders; Peritoneal Dialysis, Continuous Ambulatory; Risk Factors; Uremia

Topics: Absorptiometry, Photon; Adult; Aged; Body Composition; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Parathyroid Hormone; Proteins; Radioimmunoassay; Regression Analysis; Renal Dialysis; Sex Factors; Triglycerides; Uremia

Plasma leptin is associated with the body mass index and, more precisely, with the body fat mass. Plasma leptin has been found to be elevated in uremic patients. This study aimed at investigating the plasma leptin concentration and associations between plasma leptin, body fat mass, and glomerular filtration rate in nondiabetic predialysis uremic patients and in nondiabetic patients on chronic hemodialysis. Plasma leptin, body fat mass, and creatinine clearance were measured in 22 predialysis uremic patients, 18 hemodialysis patients, and 24 healthy control subjects. The logarithmically transformed plasma leptin concentration was closely associated with the body fat mass in all groups (r = 0.93, r = 0.83, and r = 0.72, respectively; p < 0.000001, < 0.000002 and p < 0.001, respectively). In predialysis uremic patients the plasma leptin concentration was slightly elevated as compared with controls 10.4 (3.1-59.5) ng/ml versus 5.4 (1.6-47.5) ng/ml (median and range in parentheses; p < 0. 05), whereas the plasma leptin concentration was normal in hemodialysis patients. Plasma leptin was not significantly associated with the creatinine clearance in predialysis patients. In conclusion; the glomerular filtration rate seemed to have a limited influence on the plasma leptin concentration in nondiabetic uremic subjects matched by body fat mass to controls. The plasma leptin concentration was closely associated with the body fat mass, and the leptin level might, therefore, be useful as an indicator of the fat mass in nondiabetic uremic patients.

Topics: Adipose Tissue; Body Mass Index; Body Surface Area; Case-Control Studies; Female; Humans; Leptin; Linear Models; Male; Middle Aged; Proteins; Renal Dialysis; Uremia

Marked hyperleptinaemia and metabolic acidosis are common findings in patients with chronic renal failure. In animal models, both leptin administration and acidosis reduce food intake. However, leptin causes loss of body fat, while acidosis induces muscle wasting. Whether a low pH and leptin production are related has not been studied. Leptin secretion was measured in cultured 3T3-L1 adipocytes exposed to acid or control pH for up to 96 h. In addition, serum leptin was compared between acidotic and bicarbonate-treated uraemic Wistar rats using the remnant model. Leptin levels in the culture medium were decreased at an acid pH of 7.1 compared with a control pH of 7.5 at 96 h (562+/-78 and 831+/-103 pg.48 h(-1). well(-1) respectively; mean+/-S.E.M.; P=0.037). Similarly, serum leptin in uraemic rats was found to be lower in the acidotic group than in the bicarbonate-treated group, although this observation fell just short of statistical significance (1273+/-171 compared with 2059+/-376 pg/ml; P=0.07). In conclusion, acidosis decreases leptin secretion from cultured adipocytes. Accordingly, acidotic uraemic rats seem to exhibit lower serum leptin levels than their bicarbonate-supplemented counterparts. This study is the first report providing a link between acidosis and leptin levels.

Topics: 3T3 Cells; Acidosis; Adipocytes; Animals; Female; Hydrogen-Ion Concentration; Leptin; Mice; Rats; Rats, Wistar; Uremia

We performed a cross-sectional study in a wide sample of patients with chronic renal failure undergoing conservative therapy (CTh) (n = 79), peritoneal dialysis (PD) (n = 75), and hemodialysis (HD) (n = 51), with the aim of analyzing the impact of the different modes of therapy on serum leptin levels. We used a multivariate approach, taking into consideration the potential effects of other epidemiological, dialysis-related, nutritional, and hormonal factors on serum leptin. Leptin levels were higher in patients treated with PD (median, 36 ng/mL) than in those undergoing CTh (10.8 ng/mL) or HD (5.4 ng/mL) (P < 0.0005). This difference persisted after controlling for gender, body mass index, and fasting insulin levels, suggesting that imbalances in these factors may only partially explain the differences found between the three modes of therapy. Leptin levels showed a significant negative correlation with peritoneal protein losses in PD patients but were poorly associated with factors such as proteinuria, daily peritoneal glucose absorption (PD), renal function, or adequacy of dialysis. Leptin and insulin-like growth factor-I (IGF-I) were significantly correlated in PD patients, but the study design did not allow for establishing a meaning for this correlation. In conclusion, serum leptin levels are increased in PD patients when compared with CTh or HD patients. Differences in gender distribution, fat mass, and insulin levels may partially explain these findings, but other undefined factors also may have a role in producing these results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Hemofiltration; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Kidney Function Tests; Leptin; Male; Membranes, Artificial; Metabolic Clearance Rate; Middle Aged; Peritoneal Dialysis; Renal Dialysis; Uremia

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

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

Topics: Adaptation, Physiological; Humans; Leptin; Proteins; Uremia