**Atherosclerotic Renovascular Disease**

Gen-Min Lin, Chih-Lu Han, Chung-Chi Yang and Cheng-Chung Cheng *National Defense Medical Center Taiwan* 

### **1. Introduction**

148 Chronic Kidney Disease

Wattanakit, K., Coresh, J., Muntner, P., Marsh, J. & Folsom, A. R. (2006). Cardiovascular risk

Yao, K., Kusaka, H., Sato, K., & Karasawa, A. (1994). Protective effects of KW-3902, a novel

infarction. *J Am Coll Cardiol*, 48(6), 1183-9.

in rats. *Jpn J Pharmacol, 65*(2), 167-70.

among adults with chronic kidney disease, with or without prior myocardial

adenosine A1-receptor antagonist, against gentamicin-induced acute renal failure

Atherosclerotic renovascular disease (ARVD), also known as atherosclerotic renal artery stenosis is increasingly recognized to be a cause of chronic renal failure. According to a recent administrative data regarding general population of the elderly greater than 65 years of age in the United States, the prevalence and incidence rates of ARVD were estimated 0.5% and 3.7 per each 1000 person-years respectively (Kalra et al., 2005). In addition, some epidemiological researches demonstrated that the prevalence among those with end-stage renal disease beginning renal replacement therapy was estimated from 5% to 22% (Rimmer & Gennari, 1993; Mailloux et al., 1994; Appel et al., 1995; van Ampting et al., 2003). Of note, ARVD is not only responsible to impaired kidney function but also reflects a status of patients at risk for systemic cardiovascular diseases (Kalra et al., 2005). It has been well known that a variety of risk factors for atherosclerosis share common pathway underlying atherosclerotic renal artery stenosis, coronary artery disease, and peripheral vascular disease. On the contrary, significant high-grade bilateral or isolated renal artery stenosis may cause renovascular hypertension estimating over 50% of ARVD populations by activation of renin-angiotensin-aldosterone system and lipoxygenase pathway that further deteriorate the kidney function (Romero 1997). A previous report uncovered that ARVD was estimated from 1% to 6% in patients with hypertension (Simon et al., 1972). In this regard, a vicious cycle will be established in the progression of renal arterial atherosclerosis, which is characterized by refractory hypertension, acute cardiac events (ie, heart failure, cardiogenic pulmonary edema or acute coronary syndrome), and hence leads to acute or chronic renal failure due to hypertensive or ischemic nephropathy (Buller et al., 2004). Therefore, an early alert of patients at risk for ARVD is critical in slowing down the rate of kidney function loss and providing treatment for underlying cardiovascular disease as well. In this chapter, we will fuel the readers with the classic knowledge in this field and propose the latest evidence-based medicine to manage patients with this disease.

#### **2. The pathogenesis of atherosclerosis**

Atherosclerosis is affected by the traditional risk factors including hypertension, smoking, hyperlipidemia, diabetes mellitus and family history of premature coronary artery disease systemically. Regionally, blood flow disturbances near arterial branches, bifurcations and curvatures result in complex spatiotemporal shear stresses that are associated with

Atherosclerotic Renovascular Disease 151

**PAD (%)** 


Table 1. Associations between systemic atherosclerosis and ARVD: n: number; ANG: renal angiography; CAD: coronary artery stenosis>50%; ARVD: renal artery stenosis>50%; PAD: peripheral artery stenosis>50%; NA: not available; A.A.A: abdominal aortic aneurysm;; carotid: carotid artery stenosis>50%; HR: hazard ratio; OR: odds ratio; VD: number of diseased coronary artery; § renal artery stenosis>60%; \* renal artery stenosis>75%.

According to the shear stress rule, ostial and proximal lesions are mostly encountered and 20%-50% of cases are bilateral sites in ARVD (Safian & Textor, 2001). A significant progression of ARVD was observed in 11.1% of 14,152 subjects with high cardiovascular risks within a 2.6-year period in an angiographic study (Crowley et al, 1995) and in 35%-51% from 3 to 5 years in a doplex unltrasonography study (Caps et al, 1998). From these reports, the predictors to disease progression include old age, female gender, hypertension, diabetes and the presence of significant coronary artery disease or peripheral vascular disease in which the odds ratios range from 1.2 to 2.1. On the other hand, patients with ARVD are associated with approximately 2-times risk of the occurrence of adverse coronary events and mortality as compared to those without ARVD in a long-term follow-up (Conlon et al, 2001;

As prescribed previously, patients at higher risk for atherosclerosis should receive an

Among these clinical features, the only statistically significant predictor to ARVD is the presence of abdominal bruit. The prevalence ranges from 6.5% to 31% in the healthy population (Watson & William, 1973), and 28% in hypertensive patients (Julius and Steward, 1967). However, in patients with angiographically proven ARVD, the prevalence increases up to 80% (Turnbull, 1995). Besides, the sensitivity of a systolic-diastolic abdominal bruit in the diagnosis of RAS has been reported from 39% to 63% and the specificity of 90% to 99% ((Turnbull, 1995). Thus, the presence of a systolic-diastolic bruit is highly suggestive of RAS and should be screened for, while the absence of a bruit does not exclude RAS (Rosener

Some clinical situations have to been addressed in the diffential diagnosis of ARVD (table 3).

**ARVD** 

10.4%\*

26.1%\* (bil: 19%)

**(%) Predictors** 


Hypertension, renal insufficiency, PAD

**ANG (Patient: n)**

**2.1.1 The nature course of ARVD** 

Edwards et al, 2005).

2001).

**2.2.1 Differential diagnosis** 

Kuroda, 2000

Fujii, 2006

**Age (year)**

Stroke: 346 69+11 33%

**CAD (%)** 

Stroke: 346 71+11 39% NA

**2.2 How to select patients at risk for prompt screening** 

advanced step for screening the presence of ARVD (table 2)

atherosclerosis susceptibility (Davies, 2009). In these predisposed areas, hemodynamic shear stress, the frictional force acting on the endothelial cell surface is weaker than in protected regions. Studies have identified shear stress to be an important determinant of endothelial function and phenotype. High shear stress (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective gene expression profile, while low shear stress (<4 dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates an atherogenic phenotype (Malek et al, 1999). As we know, thrombosis formation in situ and distal embolic dislodge from great vessels, determined by the burden and the stability of atherosclerosis, are the two major mechanisms leading to target organ infarction. With recent substantial evidence, systemic inflammation caused by either external stimulus such as microbial infection or internal immunologic response may trigger acute vascular events via pathogenic athroma plaque rupture. Therefore, when and how to stablize and regress the process of atherosclerosis becomes a cirtical step to prevent target organ damage.

#### **2.1 Systemic arterial atherosclerosis: the evidence from angiography and autopsy**

Advanced atherosclerosis is highly prevalent among patients with ARVD characterized by coexistence with abdominal aortic aneurysm, severe coronary artery disease, ischemic stroke and peripheral vascular disease in post-mortem and angiographic studies (Table 1).


atherosclerosis susceptibility (Davies, 2009). In these predisposed areas, hemodynamic shear stress, the frictional force acting on the endothelial cell surface is weaker than in protected regions. Studies have identified shear stress to be an important determinant of endothelial function and phenotype. High shear stress (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective gene expression profile, while low shear stress (<4 dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates an atherogenic phenotype (Malek et al, 1999). As we know, thrombosis formation in situ and distal embolic dislodge from great vessels, determined by the burden and the stability of atherosclerosis, are the two major mechanisms leading to target organ infarction. With recent substantial evidence, systemic inflammation caused by either external stimulus such as microbial infection or internal immunologic response may trigger acute vascular events via pathogenic athroma plaque rupture. Therefore, when and how to stablize and regress the process of

atherosclerosis becomes a cirtical step to prevent target organ damage.

**ANG (Patient: n)**

Crowley,

Conlon,

Leandri,

Buller,

Zhang,

Ozkan,

Liu, 2004

**Age (year)**

<sup>2001</sup>CAD: 3,987 61+9 100% NA

<sup>2004</sup>ARVD: 837 67+10 68%

**CAD (%)** 

<sup>1998</sup>CAD: 14,152 61+12 63% NA 6.3%

<sup>2006</sup>CAD: 1,200 62+10 51% NA 9.7%

<sup>2009</sup>PAD: 629 62+11 43% Aortoiliac, crural,

**2.1 Systemic arterial atherosclerosis: the evidence from angiography and autopsy** 

and peripheral vascular disease in post-mortem and angiographic studies (Table 1).

Advanced atherosclerosis is highly prevalent among patients with ARVD characterized by coexistence with abdominal aortic aneurysm, severe coronary artery disease, ischemic stroke

> **PAD (%)**

**ARVD** 

(bil: 1.3%)

9.1% (4.8%)\*

 14.4% (bil: 3.1%)

(bil: 1.7%)

femoropopliteal: 83% 9.6%§ Age, hypertension and

CAD: 141 59+10 31% NA 18.4% -CAD vs. non-CAD, HR: 2.8

<sup>2004</sup>CAD: 467 64+11 69% NA 9.0% -CAD: 2VD vs.1VD, OR: 2.8


PAD: 12%

**(%) Predictors** 


Predictors for ARVD progression:






Age, hypertension, renal insufficiency, CAD

OR: 2.1


aortoiliac stenosis


Table 1. Associations between systemic atherosclerosis and ARVD: n: number; ANG: renal angiography; CAD: coronary artery stenosis>50%; ARVD: renal artery stenosis>50%; PAD: peripheral artery stenosis>50%; NA: not available; A.A.A: abdominal aortic aneurysm;; carotid: carotid artery stenosis>50%; HR: hazard ratio; OR: odds ratio; VD: number of diseased coronary artery; § renal artery stenosis>60%; \* renal artery stenosis>75%.
