Relationship between Accessory Renal Artery and Clinical Characteristics of Middle-Aged Patients with Primary Hypertension

Objectives The association between accessory renal artery (ARA) and hypertension remains not fully understood. We observed the association between ARA and clinical characteristics among middle-aged patients with primary hypertension. Methods One hundred and sixty-two middle-aged (mean 39.82 ± 10.25 years, 58.0% male) patients with primary hypertension were enrolled, and patients underwent Computed Tomography Angiography (CTA) of renal arteries, ambulatory blood pressure monitor (ABPM), echocardiography, physical examination, and routine blood chemistry examinations. According to the CTA results, patients were divided into a non-ARA (n = 108) and ARA (n = 54) group. Direct renin concentration (DRC), plasma aldosterone concentration (PAC), ABPM, echocardiography, creatinine, and glomerular filtration rate were compared between the two groups. Results DRC (mU/L) (11.21 (5.34, 20.87) vs. 18.24 (10.32, 33.59), P=0.002) was significantly higher in the ARA group than in the non-ARA group. However, PAC (ng/dL) (98.30 (67.30, 134.00) vs. 116.50 (78.80, 137.25), P=0.103) was similar between these two groups. ABPM (mmHg) results showed that daytime (146.75 ± 17.04/95.86 ± 11.39 vs. 155.50 ± 14.76/100.48 ± 10.69, P < 0.05), night time (133.44 ± 17.50/85.28 ± 12.80 vs. 139.81 ± 14.64/89.83 ± 11.21, P < 0.05), and 24 h blood pressure (143.95 ± 15.99/93.90 ± 11.78 vs. 152.07 ± 13.85/98.11 ± 10.36, P < 0.05) were significantly higher in the ARA group than in the non-ARA group. Accordingly, echocardiographic-derived posterior left ventricular wall thickness value was higher in the ARA group than in the non-ARA group. Conclusion ARA is related to higher blood pressure and higher direct renin concentration in middle-aged patients with primary hypertension, and these patients deserve stricter blood pressure control. Our results provide important evidence for that ARA is a cause of hypertension and target organs damages.


Introduction
Hypertension is one of the major risk factors for various cardiovascular events, such as stroke, myocardial infarction, heart failure, and chronic kidney disease [1][2][3]. Unfortunately, the etiology and pathophysiology of hypertension have still not been fully elucidated [4,5]. An understanding of the pathophysiology of hypertension is essential to develop effective therapeutic strategy that contributes to the prevention of cardiovascular events [6].
ere are about 22-24% hypertensive patients having accessory renal arteries (ARAs) [7,8]. ARAs are aberrant arterial branches originating directly from the aorta and serve a small portion of renal parenchyma [9,10]. Commonly, the renal parenchyma served by ARA secretes more renin than the other parenchyma served by main renal artery as a result of smaller calibre and lower perfusion pressure of ARA [11,12]. Excessive renin contributes to abnormally elevated blood pressure through activation of the reninangiotensin system [13]. Previous studies have shown that ARA is associated with renin-dependent hypertension as well as resistant hypertension [11,14]. Nevertheless, other researchers suggest that ARA is just a vascular anomaly and not a cause of hypertension [7,15]. erefore, it is still controversial whether ARA plays a role in the pathogenesis of hypertension and the potential pathogenic mechanism underlying it.
In the present study, we observed the association between ARA and clinical characteristics among middle-aged patients with primary hypertension who underwent complete pharmacological wash-out to elimination the influence of the medicines on the sympathetic nerve system and reninangiotensin system.

Patients Selection and Design of the Study.
Between June 2017 and January 2019, 162 patients with primary hypertension undergoing Computed Tomography Angiography (CTA) of renal arteries were enrolled in this study. All the patients were between 18 and 65 years of age and underwent adequately preparation before performing CTA, echocardiography, ambulatory blood pressure monitor (ABPM), physical examination, and routine blood chemistry examinations. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, dihydropyridine calcium blockers, and clonidine were withdrawn for at least 2 weeks; aldosterone receptor antagonists were withdrawn for at least 6 weeks; diuretic was withdrawn for at least 4 weeks. Patients were prescribed nondihydropyridine calcium blocker (diltiazem) and/or α-blockers (doxazosine and terazosin) to control blood pressure. According to the CTA results, the patients were divided into a non-ARA group (n � 108) and ARA group (n � 54), and the clinical characteristics of them were collected and summarized in Table 1. Patients with the following diseases were excluded from this study: secondary hypertension, white coat hypertension, diabetes mellitus, renal artery stenosis, infection, liver or kidney dysfunction, malignant tumor, malnutrition, pregnant women, and surgery within one year. is study was approved by the Ethics Committee of First Affiliated Hospital of Dalian Medical University, and written informed consent was obtained from all the patients.

Statistical
Analysis. Data were analyzed by using the SPSS software (version 20, IBM Corporation, Armonk, NY, USA). e Kolmogorov-Smirnov test was used to determine whether the data were normally distributed. Continuous variables with normal distribution were expressed as mean ± SD and compared by the Independent-Sample t-Test. Continuous variables with nonnormal distribution were expressed as median (25 th to 75 th percentile) and compared by the nonparametric U test. Categorical variables were expressed as percentage and compared by the chisquare test. P < 0.05 was defined to be statistically significant.

Patient Population.
ere were 162 patients with primary hypertension were enrolled in this study. According to the CTA results, there were 108 patients without ARA and 54 patients with ARA. e baseline characteristics of them showed no significant differences (Table 1).

Increased Direct Renin Concentration (DRC) in Patients
with ARA. Firstly, we estimated DRC and plasma aldosterone concentration (PAC) of these patients. DRC was significantly increased in the ARA group compared with that of the non-ARA group (Table 2). Unexpectedly, PAC was only slightly upregulated in the ARA group (Table 2).

Higher Blood Pressure Measured by ABPM of Patients with
ARA. Secondly, we examined whether there was difference in the level of blood pressure between these patients. e results of ABPM showed that both SBP (systolic blood pressure) and DBP (diastolic blood pressure) in day/night/ 24 h in the ARA group were higher than those of the non-ARA group (Table 3). ese results suggested that the patients with ARA had higher blood pressure and should obtain stricter blood pressure control.

Patients with ARA Had Severe Target Organs Damages.
en, we assessed whether patients with ARA had severe target organs damages. Although interventricular septal thickness was mildly increased, there was a significant increase in left ventricular posterior wall thickness in the ARA group as measured by echocardiography (Table 4). It suggested that the geometric changes of myocardium in the patients with ARA. Furthermore, there was a slight increase in creatinine and reduction in glomerular filtration rate (GFR) in the ARA group indicating that there was mild renal dysfunction of the patients with ARA (Table 5). ese results suggested that patients with ARA had severer target organs damages.

Discussion
To investigate whether ARA was associated with hypertension accurately, middle-aged patients with primary hypertension without renal artery stenosis were enrolled in the present study. In addition, compared with previous study, patients in our study underwent complete pharmacological wash-out to elimination the influence of the medicines on the sympathetic nerve system and renin-angiotensin system. erefore, the results of the present study provided stronger evidences for the relationship between ARA and clinical characteristics among middle-aged patients with primary hypertension. e relationship between ARA and pathogenesis of hypertension was firstly suggested by the observational study conducted by Kuczera et al. in 2009 [16]. ARA is commonly longer and narrower than the main renal artery with lower perfusion pressure and higher resistance across the artery [10]. e renal parenchyma served by ARA secretes more renin than that served by main renal artery [11]. In turn, increased renin results in the activation of the renin-2 International Journal of Hypertension angiotensin system that contributes to the pathogenesis of hypertension [13]. In our study, patients with ARA had higher blood pressure with significantly increased DRC compared with those of patients without ARA, which were consistent with previous research [11]. Furthermore, we also examined PAC among these patients at the same time.
Unexpectedly, PAC was only slightly increased in the patients with ARA. e main reason for this maybe the highsalt diet of people from North China that inhibits the secretion of PAC [17,18]. ese results suggested that this     International Journal of Hypertension anatomical variant of renal artery was a cause of hypertension through excessive renin and activation of the reninangiotensin system. Considering the higher blood pressure and activation of the renin-angiotensin system in the patients with ARA, we wondered whether these patients had severe target organs damages. As we speculated, our results showed that the patients with ARA had significantly geometric changes of the myocardium and mild renal dysfunction. erefore, these results suggested that the patients with ARA should obtain stricter blood pressure control to prevent of severe cardiovascular events. We recognize some potential limitations in our study. is is a single-center study with a small sample size of middle-aged patients with primary hypertension. Multicenter research with adequate sample size, consisting of hypertensive patients and normotensive population, is essential to acquire more accurate relationship between ARA and hypertension. Besides, the volume of blood flow in ARA and blood flow perfusion of kidney is not estimated in this study. Mechanical investigations are also important to uncover the role of ARA in elevated blood pressure in the future.

Conclusions
In conclusion, we confirmed that ARA contributed to higher blood pressure in patients with primary hypertension through excessive renin and activation of the renin-angiotensin system. In addition, we verified that patients with ARA had severe target organs damages. erefore, these patients deserved stricter blood pressure control to prevent of severe cardiovascular events. Our results provided significant evidences for the aggressive treatment of hypertensive patients with ARA in daily clinical practice.

Data Availability
e data of the present study are not publicly available because they contain the personal information of the participants. ey are only available from the corresponding author on reasonable request.

Disclosure
YM and KK share the first authorship.