摘要：如何減緩腎病惡化，以降低尿毒症病人，是當前腎臟學的重要課題之一。己知阻斷血管張力素系統可以減緩慢性腎病之惡化，但並不能完全阻斷其進行。目前的趨勢在尋找較理想的藥物組合，以達到最好的腎臟保護效果。多年來，本研究團隊發現pentoxifylline (一種磷酸雙脂酶抑制劑) 在腎臟及血管平滑肌之細胞模式和動物實驗皆具有強力抗發炎、抗增生和抗纖維化的作用；而在人類腎絲球腎病變和中重度慢性腎病的初步觀察，它也能降低蛋白尿的嚴重程度。在2009 年Natural Review Nephrology 有人將它列為治療CKD 的潛力藥物之一。最近已經有小規模研究報告指出它可以減緩慢性腎病腎功能之惡化。基於這些成果，本團隊設計一個多年期的多中心合作研究模式，以前瞻性、隨機分派、雙盲、安慰劑對照設計，預計納入350 位第三至第四期慢性腎病患者，探討pentoxifylline 合併血管張力素阻斷 (Valsartan) 對慢性腎病患者的腎臟保護療效是否比單用Valsartan 更有效，同時也觀察對心血管疾病併發症之影響。全程研究為期3 年，已進行一年，本次申請為第二及第三年，主要追蹤指標為每年腎絲球過濾率（estimated Glomerular filtration rate; eGFR）之降低速率，次要追蹤指標包括血中肌酸酐升高一倍之時間、尿毒症的發生率、蛋白尿，血液和尿中發炎和纖維化相關因子之變動，包括血和尿液中TNF-α, MCP-1, TGF-β1, collagens III (amino terminal peptide ofprocollagen III) and IV, 及 fibronectin, 尿液 N-acetyl-β- glucosaminidase 濃度，以及血中fibrinogen 和 high-sensitive CPR 濃度，還有心臟衰竭、非致命性心肌梗塞、中風或暫時性缺血發作的發生率，以及整體（包括心血管相關）死亡率。期盼研究成果可以使這種合併療法，成為全世界治療慢性腎病的一種新策略。
Abstract: CKD frequently advances to ESRD, and the number of patients affected is steadilyincreasing worldwide. Taiwan has the highest incidence of treated ESRD in the world[Collins et al, 2005]. Wen et al [2008] have recently reported in a population of 462 293Taiwanese adults that the prevalence of CKD was 11·93%, a pool comparable to that of USA.In a prospective cohort of 433 patients under usual nephrologic care at National TaiwanUniversity Hospital, we have shown that the rates of GFR decline and the predictors of ESRDare comparable to that reported in the Western countries [Chiu et al, 2008]. Hence, strategiesto prevent renal progression should be implemented in all patients with CKD irrespective ofstage.To date, angiotensin blockade with angiotensin converting enzyme (ACE) inhibitor orangiotensin receptor blocker is the gold standard therapy to retard progressive renal diseases.However, blocking the renin-angiotensin system seldom achieve full remission of the disease.Therefore, alternative strategies using multidrug approaches are required to confer better ormore complete renoprotection. Over the past decade, we have demonstrated that thephosphodiesterase inhibitor pentoxifylline (PTX) in vitro is a potent anti-inflammatory,anti-proliferative, and anti-fibrotic agent capable of attenuating experimental fibrotic renaldisease in vivo, and reducing proteinuria in patients with primary glomerular disorders andmoderate to severe CKD.PTX was listed as a potential agent for treating CKD in Nature Review nephrology(2009). Most recently, PTX was found able to delay GFR decline in a small pilot study. Wethereby design this multicenter, randomized, double-blind, placebo controlled clinical trial,aiming at investigating the potential renoprotective efficacy of combined PTX andangiotensin receptor blockers (Valsartan), as compared to placebo and Valsartan, in 350patients with CKD stages 3 and 4. The research period is 3 years. This application is for the2nd and 3rd year. The primary endpoint is annual eGFR decline rate. The secondary endpointsinclude doubling time of serum creatinine, ESRD, annual changes of microalbuminuria orproteinuria, serum and urinary levels of TNF-, MCP-1, TGF-1, collagens III (aminoterminal peptide of procollagen III) and IV, and fibronectin, urinaryN-acetyl--glucosaminidase, as well as serum fibrinogen and high-sensitive CPR, anddevelopment of heart failure, nonfatal myocardial infarction, and stroke or transient ischemicattack and death from any cause and cardiovascular disease. It is our hope that data obtainedfrom this study may lead to novel therapeutic strategies in the management of CKDworldwide.
