透析患者在血管鈣化促進劑和抑制劑相關的礦物質異常以及補充鋅在這些血管鈣化的生化指標的效應

血液透析患者有異常的血液中抗氧化礦物質濃度，同時有增加的氧化壓力，可導致並促進血管鈣化。本研究的第一階段，旨在評估在血液透析患者，抗氧化礦物質與血管鈣化臨床生物標記之間的關聯。在血液透析患者 (n = 62) 和年齡和性別匹配的健康受試者( n = 30)，檢驗血液生化參數、抗氧化礦物質（硒 (Se)、鋅 (Zn)、銅 (Cu) 和鎂 (Mg)）以及幾種鈣化促進劑和抑制劑（基質 Gla 蛋白 (MGP)、纖維母細胞生長因子 23 ( FGF-23)、基質金屬蛋白酶 (MMP-2和-9) 和金屬蛋白酶組織抑制劑 (TIMP-1和-2))。與健康受試者相比，血液透析患者的血液硒和鋅濃度顯著降低，銅和鎂濃度增加，氧化壓力和發炎標記（銅/鋅比值、丙二醛 (MDA)、晚期糖基化終產物 (AGEs)、和C反應蛋白 (CRP) 增加。我們發現，血液透析患者的 MGP 濃度顯著降低，而 FGF-23、MMP-2 和-9、TIMP-和-2以及MMP-2/TIMP-2 和MMP-9/TIMP-1比值顯著升高。我們還觀察到這些礦物質的濃度與鈣化生物標記之間的顯著關係。這些結果表明，抗氧化礦物質（Se、Zn、Cu 和 Mg）的變化可能增加氧化壓力和發炎狀態，進而參與血液透析患者血管鈣化的機制。本研究的第二階段，旨在評估補充抗氧化礦物質鋅 (Zn) 對透析患者的血管鈣化生物標記的影響。接受長期血液透析或腹膜透析的患者（n = 32）接受口服葡萄糖酸鋅治療，每日劑量為78 mg(每10mg元素鋅)，持續6個月。年齡和性別匹配的健康受試者作為對照組。在基線和實驗期結束時，測量生化標記。與基線值相比，補充後血鋅濃度顯著升高。補鋅顯著降低氧化壓力和發炎標記（MDA、Cu/Zn ratio、CRP、TNF-和IL-1）；此外，這些接受鋅治療的患者血液骨橋蛋白(osteopontin)和胱抑素C(cystatin C) 濃度明顯降低，但FGF-23 和homocysteine沒有下降。此外，血鋅狀態或銅鋅比與較低水平的cystatin C密切相關。這表明充鋅可以降低血管鈣化危險因素，有潛力治療血管鈣化。

關鍵字

血管鈣化；抗氧化礦物質；氧化壓力；發炎；透析患者；鋅

並列摘要

Patients undergoing long-term hemodialysis (HD) are known to have abnormal blood concentrations of antioxidant minerals; concurrent oxidative stress can contribute to increased vascular calcification. The first stage of present study aims to evaluate the associations between circulating antioxidant minerals and clinical biomarkers of vascular calcification in HD patients. Blood biochemical parameters, antioxidant minerals (selenium (Se), zinc (Zn), copper (Cu), and magnesium (Mg)), and several promoters and inhibitors of calcification (matrix Gla protein (MGP), fibroblast growth factor-23 (FGF-23), matrix metalloproteinases (MMP-2 and -9), and tissue inhibitors of metalloproteinase (TIMP-1 and -2)) were determined in HD patients (n = 62) and age- and sex-matched healthy individuals (n = 30). Compared with healthy subjects, HD patients had significantly lower plasma concentrations of Se and Zn, increased Cu and Mg, and higher levels of oxidative stress and inflammatory markers (Cu/Zn ratios, malondialdehyde (MDA), advanced glycation end products (AGEs), and C-reactive protein (CRP)). We observed that HD patients had significantly lower concentrations of MGP and higher levels of FGF-23, MMP-2 and -9, TIMP-1 and -2, and MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios. We also observed significant relationships between the concentrations of these minerals and calcification biomarkers in HD patients. These results suggest that changes in the homeostasis of antioxidant minerals (Se, Zn, Cu, and Mg) may contribute to the effects of oxidative stress and inflammatory status, thereby participating in the mechanism for accelerated vascular calcification in patients undergoing long-term HD. The second stage of present study aims to evaluate the effect of prolonged antioxidant zinc (Zn) supplementation on some potential biomarkers of vascular calcification in subjects with chronic kidney disease. Patients on long-term hemodialysis or peritoneal dialysis (n=32) were treated by Zn gluconate with a daily dose of 78 mg for six months. Age- and sex-matched healthy individuals served as a control group. A number of biochemical markers were measured at baseline and again at end of experimental period. Compared with baseline values, post-supplementation plasma Zn concentration was significantly higher. Zn supplementation markedly reduce oxidative stress and inflammatory markers (malondialdehyde, copper to zinc ratio, C-reactive protein, tumor necrosis factor-, and interleukin-1); additionally, these patients who received Zn have obviously lower plasma concentrations of osteopontin and cystatin C, but not fibroblast growth factor 23 and homocysteine. Furthermore, plasma Zn status or copper to zinc ratio was closely associated with lower levels of cystatin C. It is suggested that low dose Zn supplementation can potentially decrease risk factors, thereby representing a potential therapeutic strategy in vascular calcification.

並列關鍵字

vascular calcification ； antioxidant minerals ； oxidative stress ； inflammation ； dialysis patients ； zinc

參考文獻

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