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Treatment of Peripheral Artery Disease in Hemodialysis Patients

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Cheng-Chieh Yen at Chia-Yi Christian Hospital
Cheng-Chieh Yen
Yi-Wen Chiu at Kaohsiung Medical University
Yi-Wen Chiu
Yueh-Han Hsu
Yueh-Han Hsu
Chiang Pei Chun at .
Chiang Pei Chun
  • .
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The incidence and prevalence of peripheral artery disease among hemodialysis patients both increase with the improvement of diagnostic methods. Therapies of noncritical ischemia status include risk factor reduction, exercise, podiatry care and medication; therapies of critical ischemia status include endovascular treatment, surgical revascularization and amputation. The prognosis is still poor nowadays regardless of contemporary therapeutic modalities. Further investigations, including pathogenesis identification, early diagnostic and therapeutic algorithms establishment, intervention timing confirmation, and multidisciplinary team approach, are warranted to improve the outcomes.
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腎臟與透析 28 卷4期，189-193 頁 (2016 年12 月)
Kidney and Dialysis Vol.28, No.4, pp. 189-193 (December, 2016)
© Taiwan Society of Nephrology & Airiti Press Inc.
血液透析
DOI: 10.6340/KD.2016.28(4).08
血液透析患者周邊血管疾病之治療
顏正杰 1、邱怡文 2、徐約翰 1,*、江培群 1、洪培豪 1
│摘要│
近年來隨著診斷方式的進步，血液透析患者周邊血管疾病的發生率與盛行率逐漸增加。非危急缺血現象
的治療包括危險因子控制、運動、足部照護和藥物等；危急缺血現象的治療包括血管內介入治療、外科血管重
建和截肢等。一旦確診罹患周邊血管疾病，無論經由何種治療方式預後都相當不佳，未來可朝探討基因表現或
病理機轉、評估早期診斷治療效益、確認最佳重建與截肢時機和多團隊參與治療等方向努力，以期改善患者的
預後。
關鍵詞：危急缺血現象、血管內介入治療、血液透析、周邊血管疾病、治療
Treatment of Peripheral Artery Disease in Hemodialysis Patients
Cheng-Chieh Yen1, Yi-Wen Chiu2, Yueh-Han Hsu1,*, Pei-Chun Chiang1, Peir-Haur Hung1
Abstract
The incidence and prevalence of peripheral artery disease among hemodialysis patients both increase with
the improvement of diagnostic methods. Therapies of noncritical ischemia status include risk factor reduction,
exercise, podiatry care and medication; therapies of critical ischemia status include endovascular treatment, surgical
revascularization and amputation. The prognosis is still poor nowadays regardless of contemporary therapeutic
modalities. Further investigations, including pathogenesis identication, early diagnostic and therapeutic algorithms
establishment, intervention timing conrmation, and multidisciplinary team approach, are warranted to improve the
outcomes.
Keywords: critical ischemia, endovascular treatment, hemodialysis, peripheral artery disease, treatment
Submitted for publication: 2016.7.25; Accepted for publication: 2016.8.18
1 戴德森醫療財團法人嘉義基督教醫院内科部；Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian
Hospital
2 高雄醫學大學附設中和紀念醫院腎臟內科；Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University
Chung-Ho Memorial Hospital
* Corresponding author: 徐約翰 Yueh-Han Hsu; E-mail: cych07023@gmail.com
顏正杰、邱怡文、徐約翰、江培群、洪培豪
Cheng-Chieh Yen, Yi-Wen Chiu, Yueh-Han Hsu, Pei-Chun Chiang, Peir-Haur Hung
190 腎臟與透析 第二十八卷 第四期 (2016)
壹、前言
周邊血管疾病 (peripheral artery disease) 又稱
為周邊血管阻塞性疾病 (peripheral artery occlusive
disease)，是指發生於「非」冠狀動脈「非」
腦動脈之血管硬化疾病。主要病理機轉為二：
一為粥樣斑塊造成的血管內皮層粥狀動脈硬化
(atherosclerosis)，二為好發於糖尿病與慢性腎臟病
患者身上的血管肌肉層鈣化沉積 [1]。早期研究顯
示血液透析患者診斷為周邊血管疾病的盛行率約在
20% 左右，近年來隨著診斷工具的進步，周邊血管
疾病的盛行率亦日漸增加 [2]，其預後隨著周邊血管
疾病的出現而下降 [3]。
其臨床表現早期是以 Fontaine stage classification
進行分類，近年來則以肢體缺血狀態區分：一類為
非危急缺血現象 (non-critical ischemia status，如無
症狀、間歇性跛行或活動後肢體疼痛等 )，另一類為
危急缺血現象 (critical ischemia status，如靜止時肢
體疼痛、傷口久不癒合或壞疽等 )。本文將著重探討
血液透析患者周邊血管疾病的治療。
貳、非危急缺血現象 (Non-Critical
Ischemia Status)
一、危險因子控制(ControlofRisk
Factors)
針對一般族群的研究顯示，周邊血管疾病的危
險因子包括年紀、男性、吸菸、糖尿病、心血管疾
病、腦血管疾病及高血脂等 ( 傳統危險因子 )；從血
管鈣化機轉觀察到血液透析病患的高血磷、高副甲
狀腺血症及低維生素 D血症 [4] 等 ( 非傳統危險因
子) 也使其罹患周邊血管疾病的機率增加。積極地
控制危險因子如血糖控制、戒菸和鈣磷控制等理論
上可以延遲病程，系統性文獻回顧證實透過戒菸能
延遲周邊血管疾病的進展 [5]。但周邊血管疾病成因
複雜，各研究間顯示的危險因子也不盡相同，目前
也沒有單純靠危險因子控制即可遏止血液透析患者
周邊血管疾病進展的前瞻性研究。
二、運動(Exercise)
針對一般族群的間歇性跛行患者所進行的綜
合分析研究顯示運動可以改善患者行走的時間和距
離，近年來針對運動的研究也擴及至血液透析患者，
顯示對於其併發症預防有正面的效果 [6]。不過目前
對於周邊血管疾病有幫助的運動種類、時間和強度
仍沒有定論，造成運動的成效不易評估，對於改善
患者的截肢率和死亡率也沒有助益。
三、足部照護(PodiatryCare)
一旦周邊血管疾病惡化造成皮膚出現傷口或壞
疽 ( 大部分都是出現於足部 )，處理不當容易造成病
患感染、截肢甚至死亡。足部照護包括衛教、血管
和神經學評估和足部醫學等，發現足部傷口後宜儘
早介入如傷口護理、抗生素使用、穿著更換或介入
療法等。研究已經證實針對血液透析患者的足部照
護能降低疾病發生率和因截肢住院的比例 [7]。
四、藥物(Medicine)
多種藥物都曾嘗試用於治療或緩解周邊血管疾
病，如抗血小板藥物、降血脂藥物、pentoxifylline
或銀杏等，可惜成效大多不顯著，有實證療效的藥
物目前只有 cilostazol 和naftidrofuryl 兩種，分述如
下：
Cilostazol 是一種第三型磷酸二酯酶抑制劑
(type III phosphodiesterase inhibitor)，存在於人類的
血小版和血管平滑肌細胞中，具有抗血小板、血管
擴張和抗血管內皮增生的效果。綜合分析研究已證
實cilostazol 針對一般族群的間歇性跛行患者能有
顯著地改善行走距離和生活品質，而血液透析患者
的周邊血管疾病在接受經皮動脈血管擴張術後合併
cilostazol 可以延長病灶再狹窄的時間 [8]。
目前僅用於歐洲的 naftidrofuryl 為第二型血清
素受體拮抗劑 (5-HT2 receptor antagonist)，具有改
善細胞內過度氧化環境的效果。綜合分析研究證實
naftidrofuryl 可在六個月的治療後顯著改善一般族
群間歇性跛行患者的行走距離 [9]，可惜目前仍缺乏
naftidrofuryl 針對血液透析病患的研究。
血液透析周邊血管疾病治療
Treatments of PAD in HD Patients
Kidney and Dialysis, Vol. 28, No. 4 (2016) 191
參、危急缺血現象 (Critical
Ischemia Status)
一、肢體保留術式(Limb-Sparing
Procedures)
此類術式顧名思義以保留患者的肢體為目標，
主要有兩種方式：
1. 血管內介入治療 (Endovascular Treatment)
血管內介入治療舊稱經皮動脈血管擴張術
(percutaneous transluminal angioplasty)，原理是以
導線穿過血管狹窄的部位，再以氣球或支架撐開血
管狹窄處以達增加血流量改善循環的效果 [10]。其
早已被證實為血液透析患者周邊血管疾病有效的治
療之一 [11] 且越早介入成效越顯著 [12]，最常見的
併發症為術後血管的再狹窄。目前治療指引建議氣
球擴張術為主，擴張術治療失敗或病灶再狹窄比例
大於 50% 時再考慮進行支架置放。血液透析患者廣
泛性分布的血管病灶也常使血管內介入治療成效不
彰，不過近年來血管內介入治療的技術層面或材質
選擇均有所進展，塗藥氣球和塗藥支架的短期成效
亦優於傳統擴張術和金屬支架，也代表未來更多治
療的可能性。
2. 外科血管重建 (Surgical Revascularization)
外科血管重建是於病灶處用自體或人工血管建
立繞道以提供遠端肢體循環的治療方式，針對較大
範圍的血管病灶理論上成效會優於經皮動脈血管擴
張術。然而血液透析患者的嚴重血管鈣化、傷口癒
合不佳、高感染及共病率都可能造成外科血管重建
成效不佳。目前針對外科血管重建介入的時間點也
無定論，大部分以壞疽未延伸至足部以上為較合適
的重建時機 [13]，不過大部分的患者 ( 尤其是糖尿
病患者 ) 重建後病程仍會持續進展至截肢，目前沒
有證據顯示外科血管重建能降低患者的死亡率。
二、截肢(Amputation)
截肢是周邊血管疾病患者最不得已的選擇，
從慢性腎臟病到末期腎病變的研究皆顯示患者截肢
後的死亡率極高 [14,15]。血液透析患者罹患周邊
血管疾病後截肢的危險因子包括心血管病變、糖尿
病、周邊神經病變及曾經出現傷口或截肢等 [16]。
大部分研究建議當壞疽延伸至足部中段時即為截
肢的適應症 [17]，不過有鑑於糖尿病患者的外科血
管重建預後不佳，也有研究建議早期截肢 (primary
amputation) 以延緩併發症，目前對於截肢的時機點
尚無定論。
當今美國心臟學會 (American Heart Association)
和歐洲心臟學會 (European Society of Cardiology) 都
有發表針對周邊血管疾病的治療指引 [18-20]。表一
為學會指引和血液透析患者周邊血管疾病治療方式
的整理。
肆、結論
近年來隨著診斷方式的進步，血液透析患者周
邊血管疾病的發生率與盛行率逐漸增加，但各種治
療方式的預後都相當不理想 [2]：主流的血管內介入
治療無法有效提升肢體保留機會，患者即使接受過
外科血管重建或是截肢，其感染住院率和死亡率仍
居高不下。未來可朝向一、重新探討周邊血管疾病
的基因表現或病理機轉等以發展新的治療方向；二、
以預防醫學的角度評估慢性腎臟病階段早期診斷治
療周邊血管疾病的效益；三、確認周邊血管疾病最
佳的重建和截肢時機；和四、結合各專業團隊參與
治療 [21] 等方向努力，以期改善血液透析患者的預
後。
顏正杰、邱怡文、徐約翰、江培群、洪培豪
Cheng-Chieh Yen, Yi-Wen Chiu, Yueh-Han Hsu, Pei-Chun Chiang, Peir-Haur Hung
192 腎臟與透析 第二十八卷 第四期 (2016)
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表一 學會指引和血液透析患者周邊血管疾病治療方式的整理
Table 1 Summary of the treatment guidelines for PAD in hemodialysis patients
周邊血管疾病治療
非嚴重肢體缺血現象 嚴重肢體缺血現象
美國心臟學會指引 [18,19] 戒菸
危險因子控制
抗血小板藥物
cilostazol
血管擴張術
外科血管重建
截肢
歐洲心臟學會指引 [20] 危險因子控制
運動
藥物治療
血管內介入療法
外科血管重建
疼痛控制
傷口照護
抗生素使用
血管內介入療法
外科血管重建
前列腺素治療
脊髓刺激療法
截肢合併復健
血液透析患者
(有文獻證據者 )
運動
足部照護
cilostazol
血管內介入療法
外科血管重建
截肢
血液透析周邊血管疾病治療
Treatments of PAD in HD Patients
Kidney and Dialysis, Vol. 28, No. 4 (2016) 193
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Lower Extremity Peripheral Artery Disease in End-stage Renal Disease: A Literature Review
Article
Full-text available
  • Jun 2016
Peripheral artery disease are more prevalent in end stage renal disease patients than the general due to suffering from both traditional and nontraditional cardiovascular risk factors. Clinical manifestations can be divided into noncritical ischemia(such as intermittent claudication) and critical ischemia(such as resting pain or gangrene). It is a challenge to diagnose peripheral artery disease among end stage renal disease patients. In noninvasive diagnostic tools, ankle brachial index is easy to perform but has poor specificity, toe brachial index is not affected by vessel calcification and brachial ankle pulse wave velocity can screen those with normal ankle brachial index; as to invasive diagnostic tools, contrast arteriography is the gold standard of diagnosis of peripheral artery disease, other tools such as intravascular ultrasonography, multi-detector computed tomography angiography, peripheral magnetic resonance angiography and Carbon dioxide angiography are practical but have its own limitations and lack of evidence among this population. Therapy of noncritical ischemia includes risk factor reduction, exercise, foot care, medication and low-density lipoprotein apheresis; therapy of critical ischemia includes thrombolysis, percutaneous transluminal angioplasty, surgical revascularization and amputation. The prognosis of end stage renal disease patients is still poor nowadays regardless of contemporary therapeutic modalities. Further investigation is needed for risk factors identification, diagnostic tool selection, preventive strategies and therapeutic algorithms establishment in earlier stages of chronic kidney disease. (J Intern Med Taiwan 2016; 27: 68-78)
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The aim of the present paper was to review the most important mechanisms explaining the possible association of vitamin D deficiency and cardiovascular diseases, focusing on recent experimental and clinical data. Low vitamin D levels favor atherosclerosis enabling vascular inflammation, endothelial dysfunction, formation of foam cells, and proliferation of smooth muscle cells. The antihypertensive properties of vitamin D include suppression of the renin-angiotensin-aldosterone system, renoprotective effects, direct effects on endothelial cells and calcium metabolism, inhibition of growth of vascular smooth muscle cells, prevention of secondary hyperparathyroidism, and beneficial effects on cardiovascular risk factors. Vitamin D is also involved in glycemic control, lipid metabolism, insulin secretion, and sensitivity, explaining the association between vitamin D deficiency and metabolic syndrome. Vitamin D deficit was associated in some studies with the number of affected coronary arteries, postinfarction complications, inflammatory cytokines and cardiac remodeling in patients with myocardial infarction, direct electromechanical effects and inflammation in atrial fibrillation, and neuroprotective effects in stroke. In peripheral arterial disease, vitamin D status was related to the decline of the functional performance, severity, atherosclerosis and inflammatory markers, arterial stiffness, vascular calcifications, and arterial aging. Vitamin D supplementation should further consider additional factors, such as phosphates, parathormone, renin, and fibroblast growth factor 23 levels.
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The mechanism of vascular calcification—A systematic review
Article
Full-text available
  • Dec 2011
  • MED SCI MONITOR
Calcification of vessels reduces their elasticity, affecting hemodynamic parameters of the cardiovascular system. The development of arterial hypertension, cardiac hypertrophy, ischemic heart disease or peripheral arterial disease significantly increases mortality in patients over 60 years of age. Stage of advancement and the extent of accumulation of calcium deposits in vessel walls are key risk factors of ischemic events. Vascular calcification is an active and complex process that involves numerous mechanisms responsible for calcium depositions in arterial walls. They lead to increase in arterial stiffness and in pulse wave velocity, which in turn increases cardiovascular disease morbidity and mortality. In-depth study and thorough understanding of vascular calcification mechanisms may be crucial for establishing an effective vasculoprotective therapy. The aim of this study was to present a comprehensive survey of current state-of-the-art research into the impact of metabolic and hormonal disorders on development of vascular calcification. Due to strong resemblance to the processes occurring in bone tissue, drugs used for osteoporosis treatment (calcitriol, estradiol, bisphosphonates) may interfere with the processes occurring in the vessel wall. On the other hand, drugs used to treat cardiovascular problems (statins, angiotensin convertase inhibitors, warfarin, heparins) may have an effect on bone tissue metabolism. Efforts to optimally control calcium and phosphate concentrations are also beneficial for patients with end-stage renal disease, for whom vessel calcification remains a major problem.
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The efficacy of a multidisciplinary team approach in critical limb ischemia
Article
  • Apr 2016
The aim of the present study was to clarify the characteristics of Japanese critical limb ischemia (CLI) patients and analyze the rates of real-world mortality and amputation-free survival (AFS) in all patients with Fontaine stage IV CLI who were treated with/without revascularization therapy by an intra-hospital multidisciplinary care team. All consecutive patients who presented with CLI at Showa University Fujigaoka Hospital between April 2008 and March 2014 were prospectively registered. The intra-hospital committee consisted of cardiologists, plastic surgeons, dermatologists, diabetologists, nephrologists, cardiovascular surgeons, and vascular technologists. The primary endpoint of this study was all-cause mortality and AFS during the follow-up period. The present study included 145 patients with Fontaine stage IV CLI. The mean age was 76.5 ± 10.2 years. The all-cause mortality rate during the follow-up period (15.5 ± 16.1 months) was 21.4 %. The AFS rate during the follow-up period (14.1 ± 16.4 months) was 58.6 %. A multivariate Cox proportional hazards regression analysis found that age >75 years and hemodialysis were significantly associated with all-cause mortality; and that age >75 years, Rutherford 6, and wound infection were significantly associated with AFS. A multidisciplinary approach and comprehensive care may improve the outcomes and optimize the collaborative treatment of CLI patients. However, all-cause mortality remained high in patients with Fontaine stage IV CLI and early referral to a hospital that can provide specialized treatment for CLI, before the occurrence of major tissue loss or infection, is necessary to avoid primary amputation.
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Risk factors for foot ulceration and lower extremity amputation in adults with end-stage renal disease on dialysis: A systematic review and meta-analysis
Article
  • May 2015
  • NEPHROL DIAL TRANSPL
Background Adults with end-stage renal disease are at increased risk of foot ulceration and lower extremity amputation. However, the central determinants of lower limb injury and loss are incompletely understood. Methods We conducted a systematic review of non-randomized studies that quantified the major risk factors for foot ulceration and amputation in adults treated with dialysis and analysed patient populations in which risks were greatest. Random-effects meta-analysis was used to generate summary estimates. Results Thirty studies (48 566 participants) were identified. Risk factors for foot ulceration and amputation included previous foot ulceration (odds ratios, OR, 17.56 and 70.13), peripheral arterial disease (OR, 7.52 and 9.12), diabetes (OR, 3.76 and 7.48), peripheral neuropathy (OR, 3.24 and 3.36) and coronary artery disease (OR, 3.92 and 2.49). Participants with foot ulceration or amputation had experienced a longer duration of diabetes (mean difference, MD, 4.04 and 6.07 years) and had lower serum albumin levels (MD, −0.23 and −0.13 g/dL). Risk factors for foot ulceration also included retinopathy (OR, 3.03), previous amputation (OR, 15.50) and higher serum phosphorus levels (MD, 0.40 mg/dL), while risk factors for amputation also included male sex (OR, 1.50), current smoking (OR, 2.26) and higher glycated haemoglobin levels (MD, 0.75%). Conclusions Dialysis patients who have markedly higher risks of ulceration or amputation include those with previous foot ulceration or amputation, peripheral neuropathy, diabetes or macrovascular disease. The temporal relationship between these risk factors and the development of foot ulceration and/or limb loss is uncertain and requires further study. Stable estimates of the key risk factors for ulceration and amputation can inform the design of future trials investigating clinical interventions to reduce the burden of lower limb disease in the dialysis population.
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Healthcare Quality Indicators of Peripheral Artery Disease Based on Systematic Reviews
Article
  • Jul 2014
Objectives Peripheral artery disease (PAD) is a major health problem whose clinical management includes multiple options regarding risk factor control, diagnosis, and medical and surgical treatment. The aim was to generate indicators based on systematic reviews to evaluate the quality of healthcare provided in PAD. Methods Electronic searches were run for systematic reviews in The Cochrane Library (Issue 6, 2011), MEDLINE, EMBASE, and other databases (up to June 2011). Conclusive systematic reviews of high methodological quality were selected to formulate clinical recommendations. Indicators were derived from clinical recommendations with moderate to very high strength of evidence as assessed by the GRADE system. Results From 1,804 reviews initially identified, 29 conclusive and high-quality systematic reviews were selected and nine clinical recommendations were formulated with a moderate to very high strength of recommendation. Six indicators were finally generated: four on pharmacological interventions, antiplatelet agents, naftidrofuryl, cilostazol, and statins; and two lifestyle interventions, exercise and tobacco cessation. No indicators were derived for diagnostic tests or surgical techniques. Most indicators targeted patients with intermittent claudication. Conclusions These quality indicators will help clinicians to assess the appropriateness of healthcare provided in PAD. The development of evidence-based indicators in PAD is limited by the lack of methodological quality of the research in this disease, the inconclusiveness of the evidence on diagnostic and surgical techniques, and the dynamic nature of the vascular diseases field.
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Benefits of Exercise Training during Hemodialysis Sessions: A Prospective Cohort Study
Article
  • Oct 2013
  • NEPHRON CLIN PRACT
Background: End-stage renal disease patients can be considered as 'cardiovascular time bombs' due to their tremendous cardiovascular risk. Our study has determined the impact of 3 months of exercise training during dialysis on some of the cardiovascular risk factors (arterial stiffness, body composition and physical performance) in a chronic hemodialyzed population. Methods: The study group (n = 19) and control group (n = 16) of chronic hemodialysis patients from Timisoara, Romania, were enrolled in a prospective cohort study. The intervention--40 min of exercise training (with non-fistula hand and both lower limbs) during each hemodialysis session for 3 months--was applied only to the study group. The measurements made before and after intervention were aortic pulse wave velocity (PWV), aortic augmentation index, return time and both central and peripheral blood pressure for arterial stiffness evaluation, using the Arteriograph Tensiomed system, body composition by multifrequency bioimpedance and physical performance (Myotest PRO system and hand dynamometer). Results: We found a significant 1-m/s reduction in PWV, a 12-second increase in return time and a 10-mm Hg reduction in both central and systolic blood pressure driven only by the exercise training. Exercise training significantly increased the skeletal muscle mass and the soft lean mass of the study group patients. Physical performance significantly improved in the study group jumping height by 1 cm, lower limbs explosive power by 3 W/kg and non-fistula hand strength prehension by 0.06 bar. Conclusions: Exercise training during dialysis has a positive effect on arterial stiffness, body composition and physical performance of chronic hemodialyzed patients.
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2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (Updating the 2005 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
Article
  • Sep 2011
  • CIRCULATION
Developed in Collaboration With the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery
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