探討慢性腎臟病病人血清中鐵調素(hepcidin)及胃飢餓素(ghrelin)濃度與心臟功能的關係

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Title:	探討慢性腎臟病病人血清中鐵調素(hepcidin)及胃飢餓素(ghrelin)濃度與心臟功能的關係 The role of serum hepcidin and ghrelin levels in cardiac function among patients with chronic kidney disease
Authors:	謝堯棚;Yao-Peng Hsieh
Contributors:	醫學院臨床醫學研究所碩士班
Keywords:	慢性腎臟病;鐵平衡;鐵調素;胃饑餓素;左心室功能;chronic kidney disease;iron homeostasis;hepcidin;ghrelin;left ventricular function
Date:	2010
Issue Date:	2010-09-29 12:17:01 (UTC+8)
Abstract:	背景︰ Hepciding 是最近發現的一種25 個氨基酸的胜肽，主要由肝細胞合成、處理並且分泌。它是維持鐵平衡方面的關鍵管理者。腎臟的清除率可能是它排泄的一種重要模式，這是血清hepcidin-25 濃度與腎絲球過濾率的相對關係比在不同的報告中並不一致。心血管疾病是有慢性腎臟病（CKD）病患的死亡的主要原因。鐵在心臟的疾病中具有關鍵作用，例如：鐵超載會引起的心肌病變，局部缺血再灌流的傷害和動脈粥狀硬化。Hepcidin 在心臟細胞的表現，於老鼠活體模式證明Hepcidin 在心臟細胞會有 mRNA 之表現和蛋白質的產生。Ghrelin 是由胃底部所分泌的一種28 個胺基酸的胜肽，跟促進食慾、增加體重及生長激素的分泌有關。此外經由動物實驗證實 ghrelin 可以降低血壓、增加心搏量、抑制心肌和內皮細胞凋亡以達到心臟保護的效果。因此，我們的目的是探討腎臟功能與血清中hepcidin 濃度的關係，以及在CKD 患者中血清hepcidin 及ghrelin 濃度與心臟功能的關係。方法︰吾人登錄146 位CKD 病患，分別由CKD 第1 階段到CKD 第5 階段，排除已進行血液或腹膜透析之患者。受試者晚上至少經過8 個小時禁食，隔日早上採血，用來分析一般生物化學數值及 hepcidin、ghrelin 濃度。吾人使用競爭性的ELISA 方式，一式兩份測量具有生物活性的hepcidin-25 與總ghrelin( acylated and des-acylated ghrelin)。心臟超音波檢查是由一位合格的心臟科專家來執行。結果︰發現血清hepcidin 的數值，在不同CKD 階段的患者，有統計學上的顯著差異。且血清中的 hepcidin 隨著CKD 的分級越高，其數值也就越高 (P= 0.002)。皮爾遜相關分析證明，血清中hepcidin 的數值與血清中的尿素氮、肌酸酐、磷酸鹽，高密度膽固醇和低密度膽固醇呈現正面的相關性，但是和腎絲球過濾率、血清白蛋白及空腹血糖呈現負相關性。血清中hepcidin 和IL-6 或者CRP 之間的相互關係，並無統計學上的關係(r = 0.183，P= 0.425； r = 0.19，P= 0.514，分別)。在多變數迴 II 歸分析過程中，hepcidin 與ferritin 是正相關性，並與腎絲球過濾率呈現負相關。Hepcidin 也與左心室質量指數(LVMI)呈現負相關 (r = -0.014，P= 0.006)。但ghrelin 與腎絲球過濾率及CKD 分期則沒有相關性；與左心室質量指數(LVMI)則呈現正相關 (r = 0.652，P= 0.003)。結論︰在CKD 病患中，血清中hepcidin 的濃度與CKD 之階段及腎功能有關，也與LVMI 呈現負相關。血清ghrelin 的濃度則與腎功能無相關但與LVMI 有正相關，這表示hepcidin 與ghrelin 可能在 CKD 病患中其心血管疾病的病態性及死亡率具有重要的角色。 Background: Hepcidin, a recently discovered 25-amino acid peptide, is mainly synthesized, processed and secreted by hepatocytes. It is the key regulator in iron homeostasis. Renal clearance may be an important way for its excretion, but the influence of estimated glomerular filtration rate (eGFR) on serum level of hepcidin-25 is inconsistent among different reports. Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Iron plays a key role in cardiac diseases, such as iron-overload cardiomyopathy, myocardial ischemia-reperfusion injury, and atherosclerosis. Cardiac expression of hepcidin was demonstrated on mRNA and protein level in vivo in a rat model. Ghrelin is a 28-amino-acid pepetide mainly secreted by gastric fundus and it can stimulate secretion of growth hormone, increase food intake and produce weight gain. In animal models, ghrelin decreased blood pressure, increased stroke volume and inhibited apoptosis of myocardiocyte and endothelium, thus protecting heart. Thus, we aim to investigate the relationship of serum hepcidin and ghrelin level to renal function and left ventricular function in patients with CKD. Methods: We enrolled a cohort of 146 CKD patients, ranging from CKD stage 1 to CKD stage 5, not requiring dialysis. After an overnight fasting for at least 8 hours, a one-time blood sample was collected for measurement biochemical data. Plasma bioactive hepcidin-25 and total ghrelin ( acylated and des-acylated forms) were measured in duplicate by competitive ELISA. Echocardiography was performed by a qualified cardiologist. Results: There was a significant difference in serum hepcidin levels between each CKD stage patients by Kruskal Wallis test ( p = 0.039). In addition, serum hepcidin levels in each CKD stage patients were lower significantly, compared with those in higher CKD stage patients by Jonckheere Terpstra test ( p=0.002). The Pearson correlation analysis demonstrated that serum hepcidin level was significantly and positively correlated with serum BUN, creatinine, phosphate, HDL cholesterol and LDL cholesterol, but negatively correlated with eGFR, serum hemoglobin, albumin and fasting blood sugar. There was no correlation between serum hepcidin and IL-6 or CRP( r = 0.183, p = 0.425; r = 0.19, p = 0.514, respectively ). In multivariate analysis, hepcidin was positively associated with ferritin and inversely correlated with eGFR. Hepcidin was also closely with left ventricle mass index (LVMI).( r = -0.014, p = 0.006). Serum ghrelin levels were not correlated with eGFR or CKD stages but positively with LVMI (r = 0.652，P= 0.003). Conclusion: The serum hepcidin level was closely associated with renal function in CKD patients. Hepcidin was also correlated inversely with LVMI and ghrelin was positively correlated with LVMI. Ghrelin and hepcidin may be crucial for cardiovascular morbidity and mortality in CKD patients.
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