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Elevated Erythropoietin Receptor and Transforming Growth Factor-ß1 Expression in Stenotic Arteriovenous Fistulae Used for Hemodialysis

NAOKI IKEGAYA^*, TATSUO YAMAMOTO^*, AKIHIRO TAKESHITA, TAKUYA WATANABE^*, KATSUHIKO YONEMURA^*, TAKEHIKO MIYAJI, KAZUHISA OHISHI, MITSUYOSHI FURUHASHI, YUKITAKA MARUYAMA and AKIRA HISHIDA^*

^* First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Third Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Maruyama Hospital, Hamamatsu, Japan.

Correspondence to Dr. Naoki Ikegaya, First Department of Medicine, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, 431-3192, Japan. Phone: +81 53 435 2261; Fax: +81 53 434 9447.

Abstract. The issue of whether recombinant human erythropoietin (rhEPO) increases thrombosis of arteriovenous (AV) fistulae used for hemodialysis remains unclear. Thrombosis often occurs at stenotic segments of fistulae where there is marked intimal hyperplasia and extracellular matrix accumulation. Increased expression of transforming growth factor-ß1 (TGF-ß1) has been shown to be involved in the development of atherosclerotic lesions by promoting intimal hyperplasia and extracellular matrix accumulation. To clarify the role of rhEPO in the development of stenosis of AV fistulae, this study examined expression of the erythropoietin receptor (EPO-R), TGF-ß1, plasminogen activator inhibitor type 1 (PAI-1), cellular fibronectin containing an extra domain A (EDA+), and TGF-ß1 mRNA, and assessed in situ rhEPO binding in tissue specimens from seven cutaneous veins and eight patent and seven stenosed portions of AV fistulae of patients undergoing dialysis. Prominent intimal hyperplasia was evident in the stenosed segments. Significant elevation in expression of EPO-R and TGF-ß1 was noted in patent AV fistulae compared to the cutaneous veins. Significant enhancement of EPO-R and TGF-ß expression was detected in the stenotic fistulae. Fibronectin EDA+ and PAI-1 expression was increased in intimal hyperplasia compared to patent fistulae and cutaneous veins. Elevated EPO-R expression was further confirmed by in situ binding of biotin-labeled rhEPO in stenosed tissue specimens. It is hypothesized that increased rhEPO binding due to elevated EPO-R expression contributes to the development of AV fistula stenosis caused by intimal hyperplasia and extracellular matrix accumulation in response to increased TGF-ß1 expression in patients receiving hemodialysis.

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