Leptin as a uremic toxin interferes with neutrophil chemotaxis
ABSTRACT 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.
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ABSTRACT: This publication reviews the currently available methods to identify uremic retention solutes, to determine their biological relevance and to quantify their removal. The analytical methods for the detection of uremic solutes have improved continuously, allowing the identification of several previously unknown solutes. Progress has been accelerated by the development of comprehensive strategies such as genomics, proteomics and the latest “omics” area, metabolomics. Those methodologies will be further refined in future. Once the concentration of solutes of interest is known based on targeted analysis, their biological relevance can be studied by means of in vitro, ex vivo, or animal models, provided those are representative for the key complications of the uremic syndrome. For this to come to pass, rigid protocols should be applied, e.g., aiming at free solute concentrations conform those found in uremia. Subsequently, the decrease in concentration of relevant solutes should be pursued by nondialysis (e.g., by influencing nutritional intake or intestinal generation, using sorbents, modifying metabolism, or preserving renal function) and dialysis methods. Optimal dialysis strategies can be sought by studying solute kinetics during dialysis. Clinical studies are necessary to assess the correct impact of those optimized strategies on outcomes. Although longitudinal studies of solute concentration and surrogate outcome studies are first steps in suggesting the usefulness of a given approach, ultimately hard outcome randomized controlled trials are needed to endorse evidence-based therapeutic choices. The nonspecificity of dialysis removal is however a handicap limiting the chances to provide proof of concept that a given solute or group of solutes has definite biological impact.Seminars in Dialysis 11/2014; 28(2). DOI:10.1111/sdi.12331 · 2.07 Impact Factor
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ABSTRACT: White adipose tissue secretes a large variety of compounds named adipokines amongst which, leptin exhibits pleiotropic metabolic actions. Leptin is an anorexigenic hormone, secreted in proportion of fat mass, with additional effects on the regulation of inflammation, cardiovascular system, immunity, hematopoiesis and bone metabolism. Chronic kidney disease (CKD) is characterized by an increase of plasma leptin concentration that may be explained by a lack of renal clearance. Hyperleptinemia plays a key role in the pathogenesis of complications associated with CKD such as cachexia, protein energy wasting, chronic inflammation, insulin resistance, cardiovascular damages and bone complications. Leptin is also involved in the progression of renal disease through its pro-fibrotic and pro-hypertensive actions. Most of the adverse effects of leptin have been documented both experimentally and clinically. Leptin may therefore be considered as an uremic toxin in CKD. The aim of this review is to summarize the pathophysiological and clinical role of leptin in in vitro studies, experimental models, as well as in patients suffering from CKD.Biochimie 07/2014; 105C. DOI:10.1016/j.biochi.2014.06.024 · 3.12 Impact Factor
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ABSTRACT: This article discusses obesity, its contribution to clinical outcomes, and the current literature on nutrition. More than one third of Americans are obese. Literature suggests that, among critically ill patients, the relationship between obesity and outcomes is complex. Obese patients may be at greater risk of developing acute respiratory distress syndrome (ARDS) than normal weight patients. Although obesity may confer greater morbidity in intensive care, it seems to decrease mortality. ARDS is a catabolic state; patients demonstrate a profound inflammatory response, multiple organ dysfunction, and hypermetabolism, often with malnutrition. The concept of pharmaconutrition has emerged. Copyright © 2014 Elsevier Inc. All rights reserved.Clinics in Chest Medicine 12/2014; DOI:10.1016/j.ccm.2014.08.005 · 2.17 Impact Factor