Adipokines in Hemodialysis Patients

描述(由申请人提供)：与非尿毒症人群相比，高体重指数(BMI)已被证明与透析患者更好的生存有关，因此脂肪被认为对透析患者有益。这就提出了这样一个问题：在非尿毒症人群中，尿毒症是否会改变介导脂肪细胞对胰岛素抵抗、血脂异常、高血压、炎症和动脉粥样硬化影响的分子信号通路。如果不是，这些分子信号的临床效果是什么？哪些治疗干预可以调节透析患者的这些信号？脂肪因子，如肿瘤坏死因子-1、白介素6、纤溶酶原激活物抑制物-1、瘦素和脂联素等，是脂肪细胞分泌的激素，介导肥胖对临床预后的影响。目前，脂肪因子是否与尿毒症的肥胖和临床疗效具有相似的关系尚不清楚。我们假设(1)尿毒症不会逆转脂肪细胞产生脂肪因子或脂肪因子对炎症、氧化应激和胰岛素抵抗的代谢影响。因此，血液透析患者肥胖与脂肪因子的关系以及脂肪因子与炎症、氧化应激和胰岛素抵抗的关系的方向与非尿毒症人群中的描述相同；以及(2)通过干预过氧化物酶体增殖物激活受体(PPAR)-3配体吡格列酮，将上调抗炎脂肪因子脂联素，下调促炎症脂肪因子、肿瘤坏死因子-1和IL-6。因此，对于超重或肥胖的糖尿病或非糖尿病慢性透析患者，吡格列酮应该减少炎症、氧化应激并保护肌肉质量。这项修订后的应用旨在(1)通过一项观察性研究进一步了解尿毒症肥胖和脂肪细胞的生物学和病理生理学；(2)通过一项干预性研究，测试尿毒症脂肪组织脂肪因子表达和血浆脂肪因子浓度与其临床代谢效应之间的因果关系。1.观察部分：这将在120名普遍存在的慢性血液透析患者(50名将接受皮下脂肪活检)中进行广泛的体重指数(BMI)检查：I.由磁共振成像(MRI)评估的内脏脂肪质量与活检皮下脂肪组织中A.脂肪因子(脂联素、肿瘤坏死因子-1和IL-6)表达的相关性；B.血浆脂肪因子水平(脂联素、TNF-1、IL-6、PAI-1和瘦素)和C.临床代谢参数(由血浆hsCRP水平指示的炎症，氧化应激，由血浆F2-异前列腺素指示，胰岛素抵抗，由稳态评估模型指示)。二、皮下脂肪因子表达与血浆脂肪因子水平及上述临床代谢参数的关系。2.干预部分：这是一项对100名超重或肥胖的普遍血液透析患者进行的PPAR3配体吡格列酮的随机安慰剂对照试验。这些患者将被随机分组，并进行24周的随访。终点将是皮下脂肪组织脂肪因子的表达、血浆脂肪因子浓度、炎症、氧化应激和胰岛素抵抗的血浆标志物以及MRI量化的大腿中部肌肉质量。这些研究将加强我们对脂肪细胞的生物学和病理生物学以及肥胖和尿毒症临床结局之间明显矛盾的理解。我们随机试验的积极结果也将为PPAR3配体药物的大规模明确干预试验铺平道路，以改善透析患者的临床结果。修订后的申请处理了审查员的所有意见。特别是，我们简化了应用程序，删除了HEMO研究部分，并广泛修改了方法部分，以澄清研究的设计和组织。公共卫生相关性：如果脂肪细胞产生有害蛋白质，旨在减少这些蛋白质产生的治疗最终将降低肥胖透析患者的发病率和死亡率。

DESCRIPTION (provided by applicant): In contrast to the non-uremic population, high body mass index (BMI) has been shown to be associated with better survival in dialysis patients and hence fat is considered to be beneficial in dialysis patients. This raises the question if uremia modifies the molecular signaling pathways that mediate the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis in the non-uremic population. If not, what are the clinical effects of these molecular signals and what therapeutic interventions could modulate these signals in dialysis patients? Adipokines, such as tumor necrosis factor-1 (TNF-1), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), leptin and adiponectin, are hormones secreted by adipocytes that mediate the effects of adiposity on clinical outcomes. Whether the adipokines bear similar relationships with adiposity and clinical effects in uremia is unclear at present. We hypothesize that (1) Uremia does not reverse the adipocyte production of adipokines or the metabolic effects of adipokines on inflammation, oxidative stress and insulin resistance. Hence, the direction of the associations of adiposity with adipokines and the associations of adipokines with inflammation, oxidative stress and insulin resistance in hemodialysis patients are the same as described in the non-uremic population; and (2) intervention with pioglitazone, a peroxisome proliferator- activated receptor (PPAR)-3 ligand, will up-regulate the anti-inflammatory adipokine adiponectin and down- regulate the pro-inflammatory adipokines, TNF-1 and IL-6. Hence, pioglitazone should decrease inflammation, oxidative stress and preserve muscle mass in overweight or obese diabetic or non-diabetic chronic dialysis patients. This revised application seeks to (1) further understand the biology and pathophysiology of adiposity and adipocytes in uremia by performing an observational study; and (2) test the causal relationships between adipose tissue adipokine expression and plasma adipokine concentrations with their clinical metabolic effects in uremia by an interventional study. 1. Observational component: This will examine in 120 prevalent chronic hemodialysis patients (50 will undergo subcutaneous fat biopsy) with a wide range of body mass index (BMI): i. the associations of visceral fat mass, as assessed by magnetic resonance imaging (MRI), with a. adipokine (adiponectin, TNF-1 and IL-6) expression in biopsied subcutaneous fat tissues b. plasma levels of adipokines (adiponectin, TNF-1, IL-6, PAI-1 and leptin) and c. clinical metabolic parameters (inflammation as indicated by plasma hsCRP levels, oxidative stress as indicated by plasma F2-isoprostanes and insulin resistance as indicated by Homeostatic Model of Assessment). ii. the associations of subcutaneous fat adipokine expression with plasma adipokine levels and the above clinical metabolic parameters. 2. Interventional component: This is a randomized placebo-controlled trial of the PPAR3 ligand pioglitazone in 100 overweight or obese prevalent hemodialysis patients. These patients will be randomized and followed for 24 weeks. The endpoints will be subcutaneous adipose tissue adipokine expression, plasma adipokine concentrations, plasma markers of inflammation, oxidative stress and insulin resistance as well as mid-thigh muscle mass quantified by MRI. These studies will enhance our understanding of the biology and pathobiology of adipocytes as well as the apparent paradox between adiposity and clinical outcomes in uremia. A positive result of our randomized trial will also pave the way for a large, definitive interventional trial of PPAR3 ligand drugs to improve the clinical outcomes of dialysis patients. The revised application has addressed all the comments of the Reviewers. In particular, we have simplified the application, deleted the HEMO Study component, and extensively revised the methods section to clarify the study design and organization. PUBLIC HEALTH RELEVANCE: If fat cells produce harmful proteins, therapy targeted towards decreasing the production of these proteins will ultimately decrease the morbidity and mortality in obese dialysis patients.