Wasse Haimanot, Rivera Angel A, Huang Rong, Martinson Deborah E, Long Qi, McKinnon William, Naqvi Nawazish, Husain Ahsan
Division of Nephrology, Emory University, Atlanta, Georgia 30322, USA.
Semin Dial. 2011 Nov-Dec;24(6):688-93. doi: 10.1111/j.1525-139X.2011.00921.x. Epub 2011 Jul 22.
The underlying inflammatory component of chronic kidney disease may predispose blood vessels to intimal hyperplasia (IH), which is the primary cause of dialysis access failure. We hypothesize that vascular pathology and markers of IH formation are antecedent to arteriovenous (AV) fistula creation. Blood, cephalic, and basilic vein segments were collected from predialysis chronic kidney disease (CKD) patients with no previous AV access and patients with end-stage renal disease (ESRD). Immunohistochemistry was performed with antibodies against mast cell chymase, transforming growth factor-beta (TGF-β) and interleukin-6 (IL-6), which cause IH. Plasma chymase was measured by ELISA. IH was present in 91% of CKD and 75% of ESRD vein segments. Chymase was abundant in vessels with IH, with the greatest expression in intima and medial layers, and virtually absent in the controls. Chymase colocalized with TGF-β1 and IL-6. Plasma chymase concentration was elevated up to 33-fold in patients with CKD versus controls and was associated with increased chymase in vessels with IH. We show that chymase expression in vessels with IH corresponds with plasma chymase concentrations. As chymase inhibition attenuates IH in animal models, and we find chymase is highly expressed in IH lesions of patients with CKD and ESRD, we speculate that chymase inhibition could have therapeutic value in humans.
慢性肾脏病潜在的炎症成分可能使血管易发生内膜增生（IH），而内膜增生是透析通路失败的主要原因。我们推测血管病变和内膜增生形成的标志物先于动静脉（AV）内瘘的建立。从既往无AV通路的透析前慢性肾脏病（CKD）患者和终末期肾病（ESRD）患者中采集血液、头静脉和贵要静脉段。用抗肥大细胞糜酶、转化生长因子-β（TGF-β）和白细胞介素-6（IL-6）的抗体进行免疫组织化学检测，这些物质可导致内膜增生。通过酶联免疫吸附测定法检测血浆糜酶。91%的CKD静脉段和75%的ESRD静脉段存在内膜增生。糜酶在有内膜增生的血管中大量存在，在内膜和中层表达最高，而在对照组中几乎不存在。糜酶与TGF-β1和IL-6共定位。与对照组相比，CKD患者的血浆糜酶浓度升高高达33倍，且与有内膜增生的血管中糜酶增加有关。我们发现有内膜增生的血管中糜酶表达与血浆糜酶浓度相对应。由于在动物模型中糜酶抑制可减轻内膜增生，且我们发现糜酶在CKD和ESRD患者的内膜增生病变中高度表达，因此我们推测糜酶抑制对人类可能具有治疗价值。
