Approach to pediatric renovascular hypertension
Article information
Abstract
Renovascular hypertension (RVH) is an important cause of hypertension in children, but it can be cured if the cause is removed in some cases. Therefore, early diagnosis and appropriate treatment are the goals of pediatricians’ care. The cause of renal artery stenosis differs in prevalence by country. Recently, the importance of diagnosing RVH as a genetic syndrome increased. This paper reviews the current literature on the diagnosis and treatment of RVH in children.
Introduction
Hypertension is a major chronic disease that is present in an estimated 28% of adults, or about 12.3 million people [1]. In contrast, the prevalence of hypertension is low in children, so blood pressure measurements are mainly conducted through school examinations. In Korea, according to Article 7 of the School Health Act, the screening is conducted for 1st and 4th graders in elementary school, 1st graders in middle school, and 1st graders in high school. The screening includes height, weight, obesity, and blood pressure. However, children younger than school age may be missed because they have difficulty cooperating with the test and are not specifically measured unless they have symptoms. Overall, the prevalence of hypertension in children is reported to be 3%–5%, with the overall prevalence of elevated blood pressure reported to be 10%–14% [2]. In Korea, a study using data from the National Health and Nutrition Examination Survey found that the prevalence of hypertension in children and adolescents aged 10 to 18 years was 10.6% in a study of 9,953 people from 2007 to 2018 based on the 2017 American Academy of Pediatrics guidelines [3].
Renovascular hypertension (RVH) accounts for 5% to 25% of pediatric hypertension cases, representing a significant proportion. Therefore, it is often referred to pediatric nephrologist and poses challenges in diagnosis and treatment depending on the patient’s age. RVH is defined as secondary hypertension caused by various diseases that interfere with the arterial flow to the renal tissue. The key to the pathogenesis of RVH is activation of the renin-angiotensin-aldosterone system, which is triggered by the increased release of renin from the juxtaglomerular apparatus [4]. RVH due to renal artery stenosis (RAS) accounts for 3%–25% of secondary hypertension in children [5]. A recent meta-analysis reported that the prevalence of secondary hypertension in primary care settings is 3.7% and that in referral settings, including pediatric nephrology clinics, is 20.1% [6]. Identifying the cause of RVH is important not only for appropriate treatment, but also because it can be an early symptom of systemic disease.
Causes of pediatric RVH
The causes of RVH in children differ significantly from those in adults, in whom this condition is mostly related to atherosclerosis. In contrast, in children, it is often caused by other diseases. In Western countries, fibromuscular dysplasia (FMD) is the leading cause of RVH in children. However, because FMD is diagnosed through histopathology and biopsies are infrequently performed on children and adolescents, its prevalence is unclear. Therefore, RAS diagnosed through imaging (without histological confirmation) is sometimes referred to as idiopathic RAS [5]. The RVH classification criteria differ in various studies. RVH is uncommon in newborns, among whom congenital anomalies and renal artery thromboembolism from umbilical artery catheterization are the primary causes [7]. The causes of RVH in children and adolescents were previously classified as FMD, a syndromic process, vasculitis, extrinsic compression, and other factors [8]. More recently, based on the development of genetic testing, RVH is also classified into diseases related to genetic syndromes, acquired factors, vasculitis, idiopathic RAS, middle aortic syndrome, and extrinsic compression (Table 1). These etiological conditions vary by country. Takayasu arteritis (TA) is the main cause in Asia and South Africa; in Korea, in addition to TA, the prevalence of RVH associated with Moyamoya disease (MMD) was also high [6,7]. Therefore, when evaluating RVH, it is necessary to approach it on the basis of prevalence of the country. It is very important to consider a family history of MMD in Korea [9,10].
Causes of pediatric renovascular hypertension
Diagnostic approach to pediatric RVH
The Academy of Pediatrics guidelines for hypertension recommend that blood pressure be measured annually for all children and adolescents starting at 3 years of age [11]. However, cooperation is difficult depending on age. Therefore, it is important to pay attention and try to measure blood pressure.
History and physical examination
History and physical examination are important for screening patients with RVH. Some literature indicates that the following symptoms are observed in patients with RVH: irritability or insufficient feeding in infants or headache, fatigue, chest pain, dyspnea, blurred vision, nausea, abdominal pain, and dizziness in pediatric patients [9,12]. However, RVH does not present with specific symptoms, making it need to measure blood pressure and conduct a thorough examination. In these patients, additional history should be collected including a detailed description of all symptoms and perinatal, nutritional, psychosocial, family, and medication history. The healthcare provider should also ask the adolescent about use of oral contraceptives, anabolic steroids, and recreational drugs. For physical examination, it is recommended to measure blood pressure in bilateral arm and leg during the first assessment, and to include anthropometric measurements [13]. Blood pressure in the lower extremities is usually 10%–20% higher than in the upper extremities [14]. Higher blood pressure in the upper extremities may be a sign of aortic stenosis and TA. Abdominal bruit usually indicates turbulent blood flow within an artery, often due to blockage or narrowing. It is known to common cause includes RAS. The child's height, weight, calculated body mass index, and age percentile are helpful in determining the individual blood pressure status [15].
Laboratory test
All patients confirmed with hypertension are recommended to undergo screening tests, including urinalysis, complete blood count, chemistry panel including electrolytes, blood urea nitrogen, creatinine, fasting plasma glucose, and a lipid profile (fasting or non-fasting to include high-density lipoprotein and total cholesterol) [5,16]. In a recent study, only 11% of patients with high blood pressure or hypertension underwent the recommended tests [17]. For patients with RVH, the aldosterone to plasma renin activity (PRA) test is necessary to screen for hyperaldosteronism. For renin and aldosterone testing, patients taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should temporarily discontinue the medication. If needed antihypertensive medication is changed, known to least interfering drugs are calcium antagonists, alpha-blockers, hydralazine, and possibly moxonidine [18]. Renin and aldosterone testing is conducted early in the morning under free sodium intake conditions, providing consistent baseline values. Baseline measurements are taken in the supine position, with known normal ranges from infants to adults. If possible, blood samples should be collected after being in the supine position and again after standing for at least 10 minutes to evaluate the changes in renin and aldosterone levels due to postural variations. According to a recent study, in patients with previously diagnosed RAS, aldosterone to PRA ratio <0.5 is likely to represent unilateral RAS, while a ratio of 3.7 or more is likely due to bilateral RAS. It is thought that these differences will arise from the following causes. Unilateral RAS, the normal function of the contralateral kidney results in relatively minor variations in renin and aldosterone levels. However, in bilateral RAS, significant increases in renin secretion from the juxtaglomerular apparatus on both sides lead to a substantial rise in aldosterone levels. Therefore, it has been reported that PRA values can be useful in suspecting unilateral versus bilateral RAS [19]. Secondary hypertension in children is mostly due to rare causes, and it is difficult to obtain meaningful results even if tests are performed. Thus, physicians tend to perform selective tests based on symptoms. However, since early diagnosis can have a significant impact on the patient's progress, it is necessary to properly perform the tests recommended in the guidelines.
Imaging tests
Imaging is essential to diagnose RVH, especially in children, in whom the diagnosis is more challenging due to their smaller blood vessels and lack of cooperation. Compared with studies in adults, the evidence in children is limited, and there is no consensus on the best method for diagnosing RVH. Doppler renal ultrasound is used as a first-line screening test for renal artery disease. However, more detailed diagnosis requires cross-sectional imaging using computed tomography angiography or magnetic resonance angiography [20]. If RVH is strongly suspected clinically but cannot be diagnosed by noninvasive methods, renal artery angiography is currently the gold standard diagnostic method [21]. However, it is not used initially for diagnosis because it is very invasive, expensive, time-consuming, and carries risks that may arise during the procedure. In addition to diagnostic purposes, renal artery angiography is performed for therapeutic purposes when surgery or percutaneous coronary angioplasty is anticipated. Among the examination methods, magnetic resonance angiography has limited value when the causative disease is suspected to be FMD because the lesions are often located in the middle and distal areas, which may not be well visualized by this method. In clinical practice, the sensitivity and specificity of each test should be considered and the test method should be selected according to the patient's age (Table 2).
Sensitivity and specificity for diagnostic image tests
Importance of genetic testing
Family history is always important in pediatric patients [10,22]. For example, two Korean studies on patients with RVH showed a high frequency of MMD among the causative diseases: five of 16 (31.3%) in one study and 10 of 25 (40.0%) in the other [9,10]. The imaging characteristics of 25 patients with RVH indicated that RAS predominantly occurred in the proximal orifice region and lacked the beaded appearance seen in FMD. Retrospective genetic analyses of patients with RAS of unknown etiology or presumed FMD and TA revealed other causal mutation-associated genes, such as RNF213 (associated with MMD), GATA6 (associated with cardiac outflow tract obstruction), ELN (associated with Williams syndrome, pulmonary stenosis, and aortic stenosis), JAG1 (associated with Alagille syndrome), GLA (associated with Fabry disease), and SMAD6 (associated with bicuspid aortic valve, aortic stenosis, and aortic aneurysm) [5,23]. For instance, RVH due to RNF213-related vasculopathy was reported in Korean children and adolescents and in Japan [24]. In this way, genetic testing can be useful in diagnosing the underlying disease in idiopathic RVH of unknown etiology. Also, genetic testing, in addition to vascular imaging findings, is expected to be helpful in the management of pediatric patients in whom invasive histological diagnosis is difficult.
Treatment of pediatric RVH
Appropriate blood pressure control is necessary for all patients with RVH to reduce the risks of target organ damage, hypertension, and cardiovascular disease in adulthood. The target blood pressure is less than the 90th percentile or less than 130/80 mmHg, whichever is lower. Pediatric patients with RVH may initially present with hypertensive emergencies due to secondary hypertension, in which case intravenous calcium channel blockers, sympathetic blockers, and vasodilators can be used. In non-emergencies, calcium channel blockers and beta blockers are commonly used for oral medication, with peripheral alpha antagonists, direct vascular smooth muscle vasodilators, and centrally acting alpha agonists also being viable options. An important factor to consider when choosing medication, especially in patients with RVH, is whether RAS is bilateral or unilateral. The use of ACE inhibitors and ARBs, which are primarily used for hypertension in children and adolescents, may be limited in cases of bilateral RAS. The use of ACE inhibitors and ARBs in bilateral RVH is limited due to the risk of acute kidney injury and hyperkalemia. In the case of diuretics, they should be used only in combination with other antihypertensive agents because they can increase renin levels and blood pressure when used alone [5]. In some cases, where blood pressure is not well controlled despite multi-drug therapy or in adolescent patients, percutaneous transluminal angioplasty (PTA) is a good treatment option if vascular access is available, and there is a possibility of complete cure in patients with RAS. However, PTA for systemic angiopathy in MMD cases was complicated by intimal hyperplasia of the smooth muscle, leading to immediate elastic rebound or progressive restenosis; there is even a risk of vessel rupture during PTA, particularly in cases of diffuse stenosis [22]. Unlike atherosclerosis in adults, PTA treatment is effective in pediatric cases in which the cause of RAS is FMD or neurofibromatosis-1 [25]. Surgical intervention is infrequently used because of small size vessels in children and technical challenges.
Conclusions
The early and accurate diagnosis and treatment of RVH are crucial in reducing target organ damage and complications. Recently, genetic testing has emerged as a helpful tool in addressing these accurate diagnostic and management challenges. The treatments of pediatric RVH include lifestyle modification, medication, PTA, and surgery. In children, PTA poses limitations based on age, causative disease, and the expert’s experience. A multidisciplinary approach is essential and must be tailored to the underlying disease, age, and complications.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author contributions
Conceptualization: YHL, HC
Formal analysis: YHL
Methodology: YHL, HC
Project administration: HC
Writing–original draft: YHL
Writing–review & editing: HC
All authors read and approved the final manuscript.