Vascular Protective Effect of Rosuvastatin in Arteriovenous Fistula
Condition: End-stage Kidney Disease; Diabetes Mellitus; Arteriovenous Fistula
MeSH terms: Kidney Diseases; Kidney Failure, Chronic; Arteriovenous Fistula; Diabetes Mellitus; Fistula
Study type: Interventional
Phase: Phase 2

Summary: 
      Background Arteriovenous (AV) fistula is the most common vascular access for long-term
      hemodialysis in the end-stage renal disease (ESRD) patients. About 25% of these patients are
      diabetes mellitus. However, the effects of hyperglycemia on the vascular function of
      arteriovenous fistula are still remained unclear. Studies have shown that blood flow in the
      AV fistula is significantly reduced in patients with diabetes mellitus. Diabetic patients
      also require a longer period of time for the maturation of AV fistula, and have slightly
      higher complication rate than non-diabetic patients. Statins have been widely shown to
      mediate several important pleiotropic effects in the improvement of vascular endothelial
      dysfunction, attenuation of inflammatory responses, stabilization of atherosclerotic plaques,
      inhibition of vascular smooth muscle proliferation, and modulation of procoagulant activity
      and platelet function.Our experimental studies in diabetic animals demonstrate that
      administration of a water-soluble statin rosuvastatin significantly improves the fistula
      flow, vascular function and luminal dilatation of AV fistula in diabetic rats by suppression
      of vascular oxidative stress and inflammatory load.

      Study hypothesis The central hypothesis of this research project is rosuvastatin mediates
      pleiotropic protective effect on vascular endothelial function and suppresses the regional
      pro-inflammatory reaction in the vasculature, therefore administration of rosuvastatin during
      the perioperative period of creation of native AV fistulas in diabetic patients with ESRD may
      potentiate the vascular function and reduce the primary failure rate of AV fistulae.
    

Detailed description: 
      Background In Taiwan, diabetic nephropathy is the second most common cause of end-stage renal
      disease (ESRD), but diabetic patients engender 12% more expense for care of dialysis than
      non-diabetic patients. ESRD patients with diabetes are also more frequently hospitalized due
      to problems such as failure of vascular access. Hemodialysis necessitates the placement of an
      arteriovenous (AV) fistula, which involves a direct anastomosis of the radial/brachial artery
      and cephalic vein. In the United States, procedures for creating the AV fistula and treatment
      of the related complication account for over 20% of hospitalizations of dialysis patients and
      cost about US$100 million annually. Two major hurdles in establishing a useable and patent AV
      fistula for dialysis are primary failure (failure of fistula to mature adequately for
      dialysis) and long-term survival of the vascular access. The reported primary failure rate
      varies from 20 to 50%. It has been shown that reduction of blood flow (>15% drop of flow over
      time) is the most critical factor for premature failure of AV fistula. Although blood flow in
      the venous site of AV fistula is also determined by the surrounding draining veins, blood
      pumped from the arterial site is the most important factor in maintaining sufficient fistula
      blood flow. However, very limited of studies have reported the effect of arterial blood flow
      on the function and patency of AV fistula. More evidences have shown that progressive failure
      of AV fistula after long-term use is due to the development of thrombosis (~80%) and stenosis
      (~20%). The mechanisms that underlie the failure of AV fistula are still poorly understood
      and there are very few, if any, specific therapeutic approaches that can increase the
      lifespan of these fistulas. Therefore, there is the critical need for experimental studies
      that seek to understand the basic mechanisms of primary failure and progressive failure of
      the AV fistula in diabetes mellitus.

      Creation of an AV fistula is the most common vascular access for ESRD patients, who require
      long-term hemodialysis. In Taiwan, about 25% of these patients have underlying diabetes
      mellitus. However, the effects of hyperglycemia on the vascular function of arteriovenous
      fistula are still remained unclear. Studies have shown that blood flow in the AV fistula is
      significantly reduced in patients with diabetes mellitus. Diabetic patients also require a
      significantly longer period of time (2 more months) for the maturation of AV fistula, and
      have slightly higher complication rate than non-diabetic patients. Diabetes mellitus has been
      shown as an independent risk factor of reduced blood flow in the native vessel arteriovenous
      fistula. Compared with patients without diabetes access blood flow was significantly lower in
      patients with diabetes mellitus (788±580 vs 1054±681 ml/min, P = 0.002). Patients with
      diabetes mellitus required a longer time until first use of their AV fistula than did
      patients without diabetes (4.4±2.9 vs 2.9±1.6 months, respectively, P= 0.02). AV
      access-related complications and need of re-intervention were higher in these patients. Most
      recently, Previous study identified that risk for reduced primary patency of AV fistula was
      increased by diabetes (Hazard Ratio, 1.54; 95% Confidence Interval, 1.14-2.07). Presence of
      diabetes is also a strong independent predictive factor for reduced initial intra-access
      blood flow within 6 months after creation of AV fistula (OR 3.5, P = 0.001). However, there
      is currently very limited effective therapeutic strategy in the prevention of loss of primary
      patency and improvement of life expectancy of AV access in patients with diabetes.

      3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are one of the
      most commonly prescribed agents in controlling hyperlipidemia. Apart from their serum
      lipid-lowering properties, statins have been widely shown to mediate several important
      pleiotropic effects, such as improvement of vascular endothelial dysfunction, attenuation of
      inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular
      smooth muscle proliferation, and modulation of procoagulant activity and platelet function.
      Among these pleiotropic effects, the protective effects on vascular endothelial function have
      mostly been highlighted. In clinical settings, statins improve cardiovascular outcomes of
      patients with atherosclerosis even in the population of normal plasma cholesterol level. The
      improvement in cardiovascular outcomes is well correlated with improved endothelial function
      by upregulation of endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO)
      bioavailability following treatment with statins. At subcellular levels, statins stabilize
      the eNOS messenger ribonucleic acid (mRNA), enhance eNOS enzymatic activity via phosphatidyl
      inositide (PI)3 kinase signaling pathway, reduce inflammatory responses in the vasculature,
      inhibit Rho isoprenylation and suppress oxidized- LDL-induced endothelin-1 expression.
      Statins have also been characterized to enhance re-endothelialization of damaged vascular
      endothelium by stimulating pre-existing endothelial cells and by mobilizing bone
      marrow-derived endothelial progenitor cells (EPCs). Collectively, stains restore vascular
      endothelial function and mediate vascular protective effects that are independent from their
      lipid-lowering effects. Although the beneficial pleiotropisms by statins are well documented
      in a variety of endothelial dysfunctional disorders, their potential therapeutic effects in
      maintaining a healthy, usable AV fistula in subjects with diabetes mellitus have been
      previously demonstrated.

      According to the knowledge of applicant, there was no published randomized control clinical
      study prospectively investigated the vascular protective effect of statins on the
      establishment of AV fistula in patients with chronic kidney disease (CKD) or ESRD. A
      long-term (up to 987 days) case-control study suggested that patients receiving statin
      therapy were associated with significantly higher overall primary patency rate of AV fistula
      after 1 year (81.7 vs 66 %) and after 2 years (71.5 vs 39.1%).

      During the past national science council (NSC)-funded years 2009-2011, the applicant
      undertook experimental study in rats with streptozotocin-induced diabetes, in which an AV
      fistula was created in each control and diabetic animals. The diabetic rats received either
      placebo or rosuvastatin (10 mg/kg/d) in chow for a period 18 days (3 days before creation of
      AV fistula and 14 after operation). Circulating cluster of differentiation (CD)133+/vascular
      endothelial growth factor receptor (KDR)+ EPCs were determined 2 weeks after creation of AV
      fistula using flow cytometry. Vascular function of AV fistula was assessed by isometric force
      testing. The expression of pro-inflammatory genes (iNOS and NADPH oxidase) and generation of
      superoxide anions in the fistula were examined. The results showed that number of EPCs was
      reduced in diabetic rats, and rosuvastatin significantly increased numbers of circulating
      EPC. Reduced blood flow and impaired endothelium-dependent relaxation in the AV fistula of
      animals with diabetes was significantly potentiated following treatment with rosuvastatin.
      Rosuvastatin also attenuated the expression of iNOS and NADPH oxidase, and generation of
      superoxide anions in the fistula tissues isolated from diabetic rats. These findings provide
      the first and very important evidence demonstrating that rosuvastatin improves blood flow and
      endothelial function of AV fistula in subjects with diabetes mellitus by attenuating the
      activity of pro-inflammatory genes and generation of superoxide anions in the remodeled
      vasculature. Based on these fascinating and encouraging findings, the applicant proposes to
      undertake clinical study in translating these experimental results to diabetic patients with
      CKD, who are scheduled to creation of AV fistula for further hemodialysis.

      Central Hypothesis and Specific Aims

      The central hypothesis of this research project is rosuvastatin mediates pleiotropic
      protective effect on vascular endothelial function and suppresses the regional
      pro-inflammatory reaction in the vasculature, therefore administration of rosuvastatin during
      the perioperative period of creation of native AV fistulas in diabetic patients with ESRD may
      potentiate the vascular function and reduce the primary failure rate of AV fistulae. Here,
      the applicant proposes to undertake a three-year research project investigating the
      therapeutic potential of rosuvastatin in the establishment of AV fistula in patients with
      diabetes mellitus. The applicant opts to test the proposed effect of rosuvastatin in diabetic
      patients. The long-term aim of this project is to develop a clinical feasible,
      endothelium-targeted therapeutic strategy for a durable AV fistula in human subjects
      necessitates hemodialysis. To achieve these research goals the applicant proposes studies
      with following specific aims:

        1. Administration of rosuvastatin protects the endothelial function in the AV fistula and
           restores the blood flow rate in the shunt of diabetic patients with ESRD, thereby
           improves the primary patent rate and early maturation of these fistulas.

        2. Administration of rosuvastatin improves the vascular function of AV fistulas in diabetic
           patients with ESRD, therefore reduces the overall shunt-related complication rate and
           the requirement for surgical re-interventions.

        3. Administration of rosuvastatin is associated with reduction of the systemic
           pro-inflammatory response and oxidative stress (levels of proinflammatory cytokines and
           other mediators in the circulation) in diabetic patients with ESRD. On the other hand,
           administration of rosuvastatin may mobilize the bone marrow-derived EPCs into systemic
           circulation, and the number of these circulating endothelial progenitors may provide
           prognostic value to the outcomes of AV fistula.

        4. Administration of rosuvastatin reduces the overall perioperative cardiovascular and
           other morbidities in diabetic patients with ESRD.

        5. Administration of rosuvastatin does not increase the incidence of statin-related
           complications (such as myopathy, abnormal liver function and neurologic deficit) in
           diabetic patients with ESRD.
    

Intervention name(s): Rosuvastatin
Intervention type(s): Drug
Intervention description(s): Arteriovenous fistula surgery was performed after 1-week treatment with placebo or Rosuvastatin (randomized, double blind). The intervention drug treatment continues for 3 more weeks after creation of AV fistula.
Other intervention name(s): Crestor
Intervention MeSH terms: Rosuvastatin Calcium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ESRD; Diabetes mellitus; Endothelial progenitor cells; Hemodialysis; rosuvastatin