Management and Outcomes of Childhood Renal Artery Stenosis and Middle Aortic Syndrome

Management and Outcomes of Childhood Renal Artery Stenosis and Middle Aortic Syndrome Abstract BACKGROUND Renal artery stenosis (RAS) in isolation or in conjunction with middle aortic syndrome (MAS) are important vascular causes of childhood hypertension. Few longitudinal studies have assessed the risk of surgical or endovascular intervention, and outcomes by etiology or extent of vascular disease. METHODS In a retrospective study of 93 children seen over 30 years with RAS and/or MAS, data on vascular involvement (isolated RAS vs. RAS with MAS), etiology (unknown, inflammatory, or genetic), and management were collected. Time to first intervention (endovascular or surgical) was assessed by Cox regression. Mixed-effects analysis examined the longitudinal change in blood pressure after intervention compared to antihypertensive medications alone. RESULTS Children were 7.0 ± 5.4 years old. Etiology was unknown in 50%, genetic in 26% and inflammatory in 24% of children. Children had isolated RAS (49%) or MAS with or without RAS (51%). Overall, 70% were managed with surgical or endovascular intervention. After adjusting for age, sex, and systolic blood pressure, children with unknown etiology had a higher risk of intervention compared to those with genetic and inflammatory diseases (hazard ratio 3.1, 95% confidence interval [CI] 1.7, 5.6). Children with RAS and MAS were less likely to receive intervention (hazard ratio 0.4, 95% CI 0.2, 0.8) than isolated RAS. Over a median follow-up of 2 years, 65% remained hypertensive. The longitudinal changes in systolic blood pressure did not differ by etiology, or between interventional and medical management. CONCLUSIONS Hypertension persists despite endovascular or surgical management of childhood RAS and MAS highlighting the importance of close monitoring and ongoing medical management. blood pressure, childhood hypertension, endovascular, hypertension, middle aortic syndrome, renal artery stenosis, renovascular disease, vascular disease Renal artery stenosis (RAS) is an important cause of renovascular hypertension in childhood. Middle aortic syndrome (MAS) is a rare disease consisting of a narrowing of the peri-renal abdominal aorta. MAS presents in conjunction with RAS in over 70% of cases in a systematic review.1,2 The anatomic involvement of the peri-renal region of the aorta and renal arteries, and the overlap in the clinical presentation, suggest that RAS and MAS may represent a shared disease process with a spectrum of affected abdominal vessels. The majority of children with RAS and/or MAS have no known cause of vascular disease, however, genetic and inflammatory diseases affecting the vasculature account for 15% and 17% of both RAS and MAS cases, respectively.1,3–5 The presenting hypertension is often severe and difficult to manage, usually requiring several antihypertensive agents.6–8 Some children may require surgical or endovascular interventions for blood pressure control.2,9–11 Interventional management is highly individualized depending on the extent of vascular involvement, response to antihypertensive therapy, and manifestations of vascular compromise such as hypoperfusion of the lower extremities or cerebrovascular disease.12–15 Many aspects of the clinical management of children with RAS and/or MAS are not well described, specifically the efficacy of interventions in controlling blood pressure, and outcomes such as re-stenosis and the need for repeated interventions. Although case series have described several techniques for the management of RAS and MAS,16 few data exist on longitudinal follow-up in children, with little to no data on changes in blood pressure over time beyond the peri-operative period. The purpose of this study is to summarize the clinical features, extent of vascular involvement, blood pressure in a cohort of children with RAS and/or MAS managed at a single center over a 30-year period. MATERIAL AND METHODS Patient population and inclusion criteria Children (age < 18) with a diagnosis of RAS and/or MAS, and managed at the Hospital for Sick Children (Toronto, Canada) between January 1986 and January 2016, were included in a retrospective cohort study. Etiology of disease was classified as genetic, inflammatory, or unknown. Genetic causes included Neurofibromatosis type I, Williams syndrome, or Alagille syndrome. Inflammatory causes included Takayasu’s arteritis or nonspecific arteritis. Etiology was unknown if no specific underlying diagnosis was made, or if the etiology was assumed to be congenital due to presentation during infancy. Genetic and inflammatory etiologies were also considered as systemic diseases. The study protocol was approved by the Research Ethics Board at the Hospital for Sick Children. Data collection Electronic medical records were reviewed for inclusion criteria, and the relevant data were collected from clinic visits, hospitalizations, and vascular imaging. Data were abstracted annually from the time of clinical presentation until the latest follow-up visit (January 2016) for concurrent children, or until discharge from nephrology clinic at age 18. Data collected included clinical characteristics, aortic and extra-aortic involvement, imaging, and endovascular or surgical interventions. Height and weight at each clinic visit were collected, and body mass index was calculated. Annual blood pressure measurements using Dinamap sphygmomanometer (Critikon, Tampa, FL) were abstracted from clinic visits. SD scores (z-score) for systolic and diastolic blood pressures and body mass index were derived from the 4th Task Force report and the Centre for Disease and Control growth charts, respectively.17,18 All blood pressure measurements were re-analyzed for the study based on the 4th Task Force report. Systolic hypertension was defined as systolic blood pressure equal to or greater than the 95th percentile for children of the same age, sex, and height.17 Arterial vascular involvement was characterized by reviewing reports from all available imaging studies. Almost all children (98%) had an abdominal computed tomography scan, angiogram, or magnetic resonance imaging available. Anatomic involvement of the abdominal aorta was described in reference to the renal arteries (supra-renal, infra-renal, or peri-renal stenosis of the abdominal aorta), using a previously described nomenclature.1 Peri-renal involvement was defined as a narrowing from the supra-renal to infra-renal portion of the aorta. Extent of aortic disease was classified as either isolated RAS or RAS/MAS if children had MAS in conjunction with RAS or isolated MAS. Management was categorized as antihypertensive therapy alone (medical) or interventional management (including surgical and endovascular procedures, or both). The procedural outcomes following endovascular interventions were classified as: uneventful (successful intervention), complicated (aortic tear, bleeding, thrombosis, stent embolization), or unsuccessful procedure (recoil of the vessel). The postoperative outcomes following surgical interventions were classified as uneventful (successful surgical outcome), or complicated (aortic tear, bleeding, thrombosis). Outcomes in terms of blood pressure control were classified as normotensive (BP <95th percentile without antihypertensive therapy), controlled blood pressure (BP <95th percentile and still required antihypertensive therapy), and hypertensive (BP >95th percentile with or without medications). Re-intervention was defined as a secondary endovascular or surgical procedure on the same artery. Re-stenosis was defined using available follow-up imaging as a narrowing of an artery that was previously dilated by an endovascular procedure. Statistical analysis Categorical data were reported as frequency and percentage, and continuous variables were expressed as the mean ± SD or median and interquartile range depending on the distribution. Comparisons among the 3 groups (unknown etiology, genetic etiology, and inflammatory etiology) were done using analysis of variance. Differences in frequencies among the 3 etiology groups were assessed using a Chi-square test or Fischer exact test, as appropriate. Kaplan–Meier survival analysis was performed to compare probabilities of receiving a first intervention (endovascular or surgical) in children with unknown, genetic, and inflammatory etiologies. The probabilities were compared using the log–rank test. Time zero was defined as the first clinic visit. Survival data were censored at year 10 of follow-up, the last available clinic date, or the last clinic date prior to transfer at age 18 years. Using Cox proportional hazards regression analysis, we compared the risk of first intervention (endovascular or surgical) by etiology of vascular disease, and by extent of vascular involvement. Multivariable adjustment for potential confounders included age and sex, baseline systolic blood pressure z-score using a forward model building approach. The proportional hazards assumption was tested using the Schoenfeld residuals. To determine the association of etiology, extent of disease, and management type (intervention or medical) with the longitudinal change in systolic blood pressure z-scores, linear mixed-effects models were used (with random slope and intercept, and unstructured covariance). Potential confounders included number of antihypertensive medications and body mass index z-score. Akaike Information Criterion and likelihood ratio test was used to assess model fit. To explore an era effect, children were stratified into 2 groups based on the year of presentation (1986–2005 and 2006–2016) and characteristics were compared using a t-test. A 2-tailed P value <0.05 was considered statistically significant. All statistical analyses were performed using Stata 13.0 (College Station, TX). RESULTS Clinical characteristics at presentation A total of 93 children met the inclusion criteria and were included in the study. The study cohort had a mean age of 7.0 (SD ± 5.4) years at presentation, and 48% were male (Table 1). Most children (62%) were clinically asymptomatic at presentation. The most common findings at presentation included hypertension (60%) and a systolic murmur (30%). Mean systolic blood pressure z-score was 2.2 ± 1.8, and mean diastolic blood pressure z-score was 1.1 ± 1.5. In terms of etiology, 50% of children had disease of unknown etiology, 26% had genetic diseases, and 24% had inflammatory disease. Of those with genetic disease, 11 children had neurofibromatosis type I, 10 children had Williams Syndrome, and the remainder had Alagille Syndrome. Inflammatory disease consisted of Takayasu’s arteritis in 21 children, and nonspecific arteritis in 1 child. Children with genetic disorders presented at a younger age compared to those with unknown disease (P = 0.01), while those with inflammatory disease presented at an older age (P = 0.01). Table 1. Aortic, visceral, and extra-aortic involvement in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis type I, Williams’ Syndrome, and Alagille Syndrome. bNot specified in imaging report. cDefined as abdominal collateral vessels. View Large Table 1. Aortic, visceral, and extra-aortic involvement in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis type I, Williams’ Syndrome, and Alagille Syndrome. bNot specified in imaging report. cDefined as abdominal collateral vessels. View Large Vascular phenotype Of the total cohort, 49% had isolated RAS, and 51% had MAS/RAS (42 had both MAS and RAS; 5 had MAS alone). Involvement of aortic and extra-aortic vessels is summarized in Table 1. Abdominal aortic disease was confined to the peri-renal region in 70% of children. There was proximal aortic involvement of the ascending aorta and aortic arch in 20% of total children, and descending thoracic involvement in 12 (13%). Almost 95% of patients had renal arterial involvement, which was bilateral in 56% of the cases. Superior mesenteric artery and celiac artery stenosis were present in 37% and 36% of children, respectively. Children with genetic or inflammatory disease had significantly more celiac and superior mesenteric artery involvement compared to the unknown etiology (46% and 64% compared to 20%, P = 0.002). Approximately 18% of children had cerebrovascular involvement including vertebral, basilar, and cerebral arteries. Carotid involvement including common, external, or internal carotid arteries was reported in 17% of children and was more prevalent in those with systemic (genetic and inflammatory) disease compared to unknown disease. Initial management and postoperative outcomes A total of 62 children received oral antihypertensive drugs upon initial presentation. The remainder of the children had systolic blood pressures less than the 95% percentile at baseline and did not require immediate antihypertensive therapy, including children with genetic diseases who were referred following screening for aortic disease. The most commonly used agents at presentation included calcium channel blockers (66%), followed by angiotensin-converting enzyme inhibitors (31%), diuretics (13%), alpha blockers (10%), and beta blockers (7%). Invasive management included surgical and endovascular procedures as summarized in Table 2. A total of 65 children (70%) received a first intervention, and 30% were managed with antihypertensive therapy alone. Children were typically managed with surgical or endovascular procedures based on nonresponse to antihypertensive therapy, escalation of antihypertensive therapy, evidence of end-organ disease, or manifestations of vascular compromise. Endovascular interventions were performed in 53 children and consisted primarily of a percutaneous transluminal angioplasty with additional stent placement in 13 children (aortic stent n = 10; renal artery n = 3). Approximately 85% of procedures were uneventful, and 13% had complications. The first follow-up visit was 9 ± 2 months following the procedure. Mean blood pressure z-score was 1.7 ± 1.6 (compared to 2.4 ± 2.0 preintervention, P = 0.7). Mean number of antihypertensive medications was 1.9 ± 1.1 (compared to 1.3 ± 1.0 preintervention, P = 0.06). Table 2. Interventional management and postoperative outcomes in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis, Williams’ Syndrome, and Alagille Syndrome. bSixty-five children had at least one intervention, including 17 children who had both a surgical and an endovascular intervention. cPTA, percutaneous transluminal angioplasty. dPostoperative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after intervention. View Large Table 2. Interventional management and postoperative outcomes in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis, Williams’ Syndrome, and Alagille Syndrome. bSixty-five children had at least one intervention, including 17 children who had both a surgical and an endovascular intervention. cPTA, percutaneous transluminal angioplasty. dPostoperative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after intervention. View Large Twenty-nine children (31%) had a surgery including reconstruction patch grafts, nephrectomy, and aortoaortic bypass. Postoperative course was uneventful in 69% of children. The first postoperative clinic visit was 8 ± 2 months following the procedure. Mean blood pressure z-score after surgery was 1.9 ± 1.5 (compared to 2.8 ± 2.0 before surgery, P = 0.2). Mean number of antihypertensives used was 1.9 ± 1.1 (compared to 1.2 ± 1.0 preintervention, P = 0.01). A total of 17 children had both an endovascular and a surgical procedure. Over the observation period, 2 children died of hypoxic-ischemic injury at presentation, and vessel necrosis following an aortic stent placement. The probability of receiving a first intervention differed significantly by etiology of disease (Figure 1). Children with unknown etiology had the highest cumulative probability of receiving surgical or endovascular, followed by those with inflammatory disease, and the lowest probability in those with genetic conditions (P log–rank = 0.002; Figure 1). Median time to intervention was 0.7 [0.1–1.9] years from first clinic visit in children with unknown disease, 1.7 [0.3–5.2] years in those with inflammatory disease, and 2.9 [0.8–4.7] years in those with genetic disease. After adjusting for age, sex, and systolic blood pressure z-score, children with unknown disease had a 3 times higher risk of receiving an intervention compared to those with systemic disease (hazard ratio 3.1, 95% confidence interval [CI] 1.7, 5.6) by Cox regression. Those with RAS/MAS had a 60% lower risk of receiving invasive management compared to those with isolated RAS (hazard ratio 0.4, 95% CI 0.2, 0.8) after similar adjustment. Figure 1. View largeDownload slide Interventional procedures (endovascular or surgical) among children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) of unknown, genetic, or inflammatory etiologies. Figure 1. View largeDownload slide Interventional procedures (endovascular or surgical) among children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) of unknown, genetic, or inflammatory etiologies. Follow-up Median follow-up was 1.9 [0.4–4.7] years. Figure 2 summarizes annual systolic blood pressure z-score over the longitudinal follow-up period stratified by medical management or intervention. Blood pressures remained elevated over the follow-up period in both children receiving medical management alone and those who underwent interventions, with a median blood pressure z-score of 2.0 [1.1–3.2]. Blood pressure z-score, presence of hypertension, and number of antihypertensive medications at last follow-up compared to baseline values are presented in Table 3. By linear mixed-effects analysis, the longitudinal change in systolic blood pressure Z-score was higher in those with MAS/RAS compared to those with isolated RAS (unadjusted β = 1.3, 95% CI 0.6, 1.9), even after adjustment for number of antihypertensive agents (adjusted β = 1.2, 95% CI 0.6, 1.8). The longitudinal change in systolic blood pressures did not differ by etiology, or between medical and interventional management. There were no differences in outcomes in terms of residual hypertension and use of antihypertensive medications between those receiving interventional management compared to those managed medically (Supplementary Table 1). Table 3. Blood pressures and antihypertensive therapy use in 93 children with RAS and/or MAS at clinical presentation (baseline) and last follow-up by underlying etiology, extent of disease, and management type Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis; RAS/MAS: RAS with MAS (n = 42) or MAS alone (n = 5). View Large Table 3. Blood pressures and antihypertensive therapy use in 93 children with RAS and/or MAS at clinical presentation (baseline) and last follow-up by underlying etiology, extent of disease, and management type Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis; RAS/MAS: RAS with MAS (n = 42) or MAS alone (n = 5). View Large Figure 2. View largeDownload slide Systolic blood pressure z-score at annual follow-up over the study period in children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) receiving medical management (antihypertensive therapy) and interventional management (endovascular and surgical interventions). Figure 2. View largeDownload slide Systolic blood pressure z-score at annual follow-up over the study period in children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) receiving medical management (antihypertensive therapy) and interventional management (endovascular and surgical interventions). Approximately 66% of children were still hypertensive at follow-up, with a mean systolic blood pressure z-score of 2.4 ± 1.6 (Table 3). Approximately 17% were normotensive without requiring any antihypertensive medications, and 17% had controlled blood pressure with antihypertensive therapy. Mean number of antihypertensive agents used was 1.2 ± 1.0 (compared to 1.9 ± 1.0 immediately post-intervention, P = 0.03), and did not differ by etiology or by extent of vascular disease. Of those who received a primary endovascular or surgical intervention, 33 (51%) had a re-stenosis of the same vessel (following a first endovascular intervention), and 25 (39%) required a re-intervention. Re-interventions were more common among those with genetic and inflammatory disease compared to children with unknown disease (58% and 69% vs. 23%, respectively, P < 0.001). There was no progression from isolated RAS to MAS/RAS and no additional aortic branch involvement. Era effect The majority of children diagnosed with RAS and/or MAS presented in the last 10 years of the study period (Supplementary Figure 1). Supplementary Table 2 compares the characteristics of children presenting during the first (1986–2005, n = 41) and second (2006–2016, n = 52) periods of the reported experience. Children in the earlier period presented at a younger age (6 ± 5 vs. 8 ± 6, respectively, P = 0.04). The earlier time period had a higher proportion of children undergoing surgical intervention and a higher proportion of re-interventions. DISCUSSION In a comprehensive review of childhood RAS and/or MAS, our results demonstrate that even after conservative medical or interventional management, more than two thirds of children have persistent hypertension requiring long-term antihypertensive management. Most children with RAS and/or MAS undergo endovascular or surgical interventions to control blood pressure, with longer periods of time prior to intervention in children with genetic and inflammatory diseases than those with no known etiology. The majority of children have no known cause of disease, with the extent of vessel involvement relatively confined to the peri-renal aorta. Children with genetic and inflammatory disease have additional vascular involvement including visceral and proximal aortic branches. Despite the increased recognition of the clinical presentation of RAS and MAS in children over the past decade, there are many gaps in our understanding of this disease. One of the main challenges in managing RAS and MAS is the unknown pathogenesis of the vascular disease. This is crucial given that etiology of disease greatly influences the choice and timing of interventional management in children. Interventions are often delayed during the acute phase of inflammatory diseases, and in children with genetic causes given the potential risk associated with invasive management, and concern of potential progression due to the underlying vasculopathy. A diagnosis of exclusion often attributed to RAS and MAS is fibromuscular dysplasia.19 In most reported series of childhood RAS, there is little evidence of the classic angiographic appearance of beading, a common feature of medial fibroplasia in adults.20 The vascular involvement in adult fibromuscular dysplasia compared to pediatric cases of RAS/MAS is clearly different, with more cerebrovascular and carotid disease in adults compared to isolated RAS or confined peri-renal aortic disease in children,1,21,22 consistent with the findings in our cohort. In a systematic review of childhood MAS, we demonstrated that aortic involvement is predominantly confined to the peri-renal segment of the aorta, with a high propensity for bilateral RAS.1 Our current study corroborates the anatomical classification based on the systematic review, as there are cases of isolated RAS but almost all MAS cases include RAS. Importantly, we found no evidence of vascular disease progression in terms of new aortic involvement or expanding vascular involvement of other abdominal vessels. Similar to other studies, we observed re-stenosis of vessels following endovascular intervention,21–25 which was often confined to the same treated vessel. It is worth noting, however, that we did not conduct systematic imaging of nondiseased vessels such as the carotid arteries. Future studies should confirm these findings with more systematic vascular imaging on follow-up. An important finding is the persistent hypertension in children with renovascular disease following endovascular and surgical management. Given that the majority of children still require antihypertensive management despite partial or complete relief of arterial narrowing,1,3 defining treatment success as complete resolution of hypertension may not be realistic in children with RAS and/or MAS. In contrast to other studies that report complete resolution of hypertension in children,14,26 we found that over two thirds of children had persistent hypertension for a median of 2 years after the initial procedure. These differences may be due to the greater heterogeneity of the vascular involvement, as well as the higher proportion of systemic diseases in our cohort compared to other studies. Only 18% of children in our cohort had complete normalization of blood pressure without any need for medications. Similar proportions are reported in other series of childhood RAS and MAS.3,26 The etiology of the persistent hypertension remains unclear, with hypotheses that include an underlying arteriopathy, or an effect of residual narrowing on proximal hemodynamics.27–30 In contrast to published case series from other centers, diagnostic angiography and follow-up catheter-based imaging are not routinely performed in our pediatric cohort.26 Rather, follow-up imaging mainly consists of abdominal ultrasound until worsening of symptoms or evidence of end-organ disease merit further cross-sectional imaging (computed tomography angiography or magnetic resonance angiography) or a secondary intervention. Clear guidelines for the diagnosis and management of renovascular hypertension in children are not defined and are challenging to standardize given the heterogeneity of this population in terms of etiology, response to medications, and vascular involvement. Previous studies have advocated residual hypertension with 2 or more antihypertensive agents as criteria for endovascular intervention,26 however, the potential benefit of blood pressure lowering with angioplasty needs to be balanced against the associated risk of repeated interventions especially given the high prevalence of persistent hypertension even after a successful endovascular procedure. This study has some limitations inherent to its retrospective design. Children underwent variable imaging modalities and of different vascular beds, which may have limited the extent of phenotypic description. Additionally, our experience spans 30 years during which temporal trends may have occurred in antihypertensive management and indications for endovascular or surgical intervention, as well as clinical follow-up. Given the anatomic variability and variation in the degree of extra-aortic involvement, surgical management often needs to be individualized. Antihypertensive management is also not standardized and may vary by prescribing physician, but statistical adjustment for number of medications was undertaken. Although there was no improvement in systolic blood pressures over 2 years of follow-up, there may have been changes in end-organ disease, symptoms, and quality of life. Medical or invasive management can have benefit in these areas that this study was not able to capture. Further, manual blood pressure measurements were not consistently reported in clinical records, thus lacking precision. However, repeated measures in individuals were used to ascertain elevated blood pressure. Lastly, as our median follow up is 2 years, we are not able to comment on long-term outcomes in this population. Despite these limitations, our results demonstrate important clinical observations from one of the largest cohorts of childhood RAS and MAS and emphasize the need for close monitoring of this high-risk group. Our cohort has a number of strengths in that all children with MAS and/or RAS were included regardless of etiology. Further, the study highlights the differences in the time to intervention by etiology. This may have clinical implications as intervention with genetic disorders could be considered sooner given that progression of vascular disease was not common. Additionally, longitudinal analysis of repeated blood pressure measurements demonstrated persistent hypertension even after successful interventional management. Further studies are needed to evaluate the effect of this persistent hypertension on end-organ cardiac disease. CONCLUSION RAS and/or MAS, often coexisting, are important causes of hypertension in children. The vascular involvement is localized to the peri-renal aorta, and the majority of cases have no known etiology. Children with inflammatory and genetic diseases and those with more extensive vascular involvement are less likely to have endovascular or surgical interventions. We found that residual hypertension persists in more than two thirds of children after both medical and interventional therapy. Our findings highlight the importance of blood pressure control and need for close monitoring of children with RAS and/or MAS even after interventions. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. ACKNOWLEDGMENT This study was supported by the Banting & Best Scholarship from the Canadian Institute for Health Research (CGS-M) (http://www.cihr-irsc.gc.ca) through the Frederick Banting and Charles Best Canada Graduate Scholarship. REFERENCES 1. Rumman RK , Nickel C , Matsuda-Abedini M , Lorenzo AJ , Langlois V , Radhakrishnan S , Amaral J , Mertens L , Parekh RS . 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Idiopathic mid-aortic syndrome in children . Pediatr Nephrol 2008 ; 23 : 1135 – 1142 . Google Scholar CrossRef Search ADS PubMed 6. Lal A , Kumar Garg M , Galwa RP , Khandelwal N . Middle-aortic syndrome—an unusual case of progressive refractory hypertension . Eur J Radiol 2009 ; 70 : e41 – e43 . Google Scholar CrossRef Search ADS 7. ten Dam K , van der Palen RL , Tanke RB , Schreuder MF , de Jong H . Clinical recognition of mid-aortic syndrome in children . Eur J Pediatr 2013 ; 172 : 413 – 416 . Google Scholar CrossRef Search ADS PubMed 8. Nasser H , Nehme GD , Dumitriu D , Galloy MA , Bourquard R , Claudon M , Andre JL . Idiopathic midaortic syndrome: normalization of blood pressure on medication . Pediatr Nephrol 2012 ; 27 : 313 – 316 . Google Scholar CrossRef Search ADS PubMed 9. Stanley JC , Fry WJ . Pediatric renal artery occlusive disease and renovascular hypertension. Etiology, diagnosis, and operative treatment . Arch Surg 1981 ; 116 : 669 – 676 . Google Scholar CrossRef Search ADS PubMed 10. Stanley JC , Zelenock GB , Messina LM , Wakefield TW . Pediatric renovascular hypertension: a thirty-year experience of operative treatment . J Vasc Surg 1995 ; 21 : 212 – 226 ; discussion 226. Google Scholar CrossRef Search ADS PubMed 11. Upchurch GR Jr , Henke PK , Eagleton MJ , Grigoryants V , Sullivan VV , Wakefield TW , Jacobs LA , Greenfield LJ , Stanley JC . Pediatric splanchnic arterial occlusive disease: clinical relevance and operative treatment . J Vasc Surg 2002 ; 35 : 860 – 867 . Google Scholar CrossRef Search ADS PubMed 12. Stanley JC , Criado E , Upchurch GR Jr , Brophy PD , Cho KJ , Rectenwald JE , Kershaw DB , Williams DM , Berguer R , Henke PK , Wakefield TW ; Michigan Pediatric Renovascular Group . Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children . J Vasc Surg 2006 ; 44 : 1219 – 1228 ; discussion 1228. Google Scholar CrossRef Search ADS PubMed 13. De Bakey ME , Garrett HE , Howell JF , Morris GC Jr . Coarctation of the abdominal aorta with renal arterial stenosis: surgical considerations . Ann Surg 1967 ; 165 : 830 – 843 . Google Scholar CrossRef Search ADS PubMed 14. Sandmann W , Dueppers P , Pourhassan S , Voiculescu A , Klee D , Balzer KM . Early and long-term results after reconstructive surgery in 42 children and two young adults with renovascular hypertension due to fibromuscular dysplasia and middle aortic syndrome . Eur J Vasc Endovasc Surg 2014 ; 47 : 509 – 516 . Google Scholar CrossRef Search ADS PubMed 15. Poupalou A , Salomon R , Boudjemline Y , Allain-Launay E , Aigrain Y , Chardot C . Aortic bypass and bilateral renal autotransplantation for mid-aortic syndrome . Pediatr Nephrol 2013 ; 28 : 1871 – 1874 . Google Scholar CrossRef Search ADS PubMed 16. Stanley JC , Criado E , Eliason JL , Upchurch GR Jr , Berguer R , Rectenwald JE . Abdominal aortic coarctation: surgical treatment of 53 patients with a thoracoabdominal bypass, patch aortoplasty, or interposition aortoaortic graft . J Vasc Surg 2008 ; 48 : 1073 – 1082 . Google Scholar CrossRef Search ADS PubMed 17. Falkner B , Daniels SR . Summary of the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents . Hypertension 2004 ; 44 : 387 – 388 . Google Scholar CrossRef Search ADS PubMed 18. Kuczmarski RJ , Ogden CL , Guo SS , Grummer-Strawn LM , Flegal KM , Mei Z , Wei R , Curtin LR , Roche AF , Johnson CL . 2000 CDC Growth Charts for the United States: methods and development . Vital Health Stat 11 2002 ; 246: 1 – 190 . 19. Tullus K , Brennan E , Hamilton G , Lord R , McLaren CA , Marks SD , Roebuck DJ . Renovascular hypertension in children . Lancet 2008 ; 371 : 1453 – 1463 . Google Scholar CrossRef Search ADS PubMed 20. Tullus K . 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Google Scholar CrossRef Search ADS PubMed © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Management and Outcomes of Childhood Renal Artery Stenosis and Middle Aortic Syndrome

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Oxford University Press
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© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0895-7061
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1941-7225
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10.1093/ajh/hpy014
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Abstract

Abstract BACKGROUND Renal artery stenosis (RAS) in isolation or in conjunction with middle aortic syndrome (MAS) are important vascular causes of childhood hypertension. Few longitudinal studies have assessed the risk of surgical or endovascular intervention, and outcomes by etiology or extent of vascular disease. METHODS In a retrospective study of 93 children seen over 30 years with RAS and/or MAS, data on vascular involvement (isolated RAS vs. RAS with MAS), etiology (unknown, inflammatory, or genetic), and management were collected. Time to first intervention (endovascular or surgical) was assessed by Cox regression. Mixed-effects analysis examined the longitudinal change in blood pressure after intervention compared to antihypertensive medications alone. RESULTS Children were 7.0 ± 5.4 years old. Etiology was unknown in 50%, genetic in 26% and inflammatory in 24% of children. Children had isolated RAS (49%) or MAS with or without RAS (51%). Overall, 70% were managed with surgical or endovascular intervention. After adjusting for age, sex, and systolic blood pressure, children with unknown etiology had a higher risk of intervention compared to those with genetic and inflammatory diseases (hazard ratio 3.1, 95% confidence interval [CI] 1.7, 5.6). Children with RAS and MAS were less likely to receive intervention (hazard ratio 0.4, 95% CI 0.2, 0.8) than isolated RAS. Over a median follow-up of 2 years, 65% remained hypertensive. The longitudinal changes in systolic blood pressure did not differ by etiology, or between interventional and medical management. CONCLUSIONS Hypertension persists despite endovascular or surgical management of childhood RAS and MAS highlighting the importance of close monitoring and ongoing medical management. blood pressure, childhood hypertension, endovascular, hypertension, middle aortic syndrome, renal artery stenosis, renovascular disease, vascular disease Renal artery stenosis (RAS) is an important cause of renovascular hypertension in childhood. Middle aortic syndrome (MAS) is a rare disease consisting of a narrowing of the peri-renal abdominal aorta. MAS presents in conjunction with RAS in over 70% of cases in a systematic review.1,2 The anatomic involvement of the peri-renal region of the aorta and renal arteries, and the overlap in the clinical presentation, suggest that RAS and MAS may represent a shared disease process with a spectrum of affected abdominal vessels. The majority of children with RAS and/or MAS have no known cause of vascular disease, however, genetic and inflammatory diseases affecting the vasculature account for 15% and 17% of both RAS and MAS cases, respectively.1,3–5 The presenting hypertension is often severe and difficult to manage, usually requiring several antihypertensive agents.6–8 Some children may require surgical or endovascular interventions for blood pressure control.2,9–11 Interventional management is highly individualized depending on the extent of vascular involvement, response to antihypertensive therapy, and manifestations of vascular compromise such as hypoperfusion of the lower extremities or cerebrovascular disease.12–15 Many aspects of the clinical management of children with RAS and/or MAS are not well described, specifically the efficacy of interventions in controlling blood pressure, and outcomes such as re-stenosis and the need for repeated interventions. Although case series have described several techniques for the management of RAS and MAS,16 few data exist on longitudinal follow-up in children, with little to no data on changes in blood pressure over time beyond the peri-operative period. The purpose of this study is to summarize the clinical features, extent of vascular involvement, blood pressure in a cohort of children with RAS and/or MAS managed at a single center over a 30-year period. MATERIAL AND METHODS Patient population and inclusion criteria Children (age < 18) with a diagnosis of RAS and/or MAS, and managed at the Hospital for Sick Children (Toronto, Canada) between January 1986 and January 2016, were included in a retrospective cohort study. Etiology of disease was classified as genetic, inflammatory, or unknown. Genetic causes included Neurofibromatosis type I, Williams syndrome, or Alagille syndrome. Inflammatory causes included Takayasu’s arteritis or nonspecific arteritis. Etiology was unknown if no specific underlying diagnosis was made, or if the etiology was assumed to be congenital due to presentation during infancy. Genetic and inflammatory etiologies were also considered as systemic diseases. The study protocol was approved by the Research Ethics Board at the Hospital for Sick Children. Data collection Electronic medical records were reviewed for inclusion criteria, and the relevant data were collected from clinic visits, hospitalizations, and vascular imaging. Data were abstracted annually from the time of clinical presentation until the latest follow-up visit (January 2016) for concurrent children, or until discharge from nephrology clinic at age 18. Data collected included clinical characteristics, aortic and extra-aortic involvement, imaging, and endovascular or surgical interventions. Height and weight at each clinic visit were collected, and body mass index was calculated. Annual blood pressure measurements using Dinamap sphygmomanometer (Critikon, Tampa, FL) were abstracted from clinic visits. SD scores (z-score) for systolic and diastolic blood pressures and body mass index were derived from the 4th Task Force report and the Centre for Disease and Control growth charts, respectively.17,18 All blood pressure measurements were re-analyzed for the study based on the 4th Task Force report. Systolic hypertension was defined as systolic blood pressure equal to or greater than the 95th percentile for children of the same age, sex, and height.17 Arterial vascular involvement was characterized by reviewing reports from all available imaging studies. Almost all children (98%) had an abdominal computed tomography scan, angiogram, or magnetic resonance imaging available. Anatomic involvement of the abdominal aorta was described in reference to the renal arteries (supra-renal, infra-renal, or peri-renal stenosis of the abdominal aorta), using a previously described nomenclature.1 Peri-renal involvement was defined as a narrowing from the supra-renal to infra-renal portion of the aorta. Extent of aortic disease was classified as either isolated RAS or RAS/MAS if children had MAS in conjunction with RAS or isolated MAS. Management was categorized as antihypertensive therapy alone (medical) or interventional management (including surgical and endovascular procedures, or both). The procedural outcomes following endovascular interventions were classified as: uneventful (successful intervention), complicated (aortic tear, bleeding, thrombosis, stent embolization), or unsuccessful procedure (recoil of the vessel). The postoperative outcomes following surgical interventions were classified as uneventful (successful surgical outcome), or complicated (aortic tear, bleeding, thrombosis). Outcomes in terms of blood pressure control were classified as normotensive (BP <95th percentile without antihypertensive therapy), controlled blood pressure (BP <95th percentile and still required antihypertensive therapy), and hypertensive (BP >95th percentile with or without medications). Re-intervention was defined as a secondary endovascular or surgical procedure on the same artery. Re-stenosis was defined using available follow-up imaging as a narrowing of an artery that was previously dilated by an endovascular procedure. Statistical analysis Categorical data were reported as frequency and percentage, and continuous variables were expressed as the mean ± SD or median and interquartile range depending on the distribution. Comparisons among the 3 groups (unknown etiology, genetic etiology, and inflammatory etiology) were done using analysis of variance. Differences in frequencies among the 3 etiology groups were assessed using a Chi-square test or Fischer exact test, as appropriate. Kaplan–Meier survival analysis was performed to compare probabilities of receiving a first intervention (endovascular or surgical) in children with unknown, genetic, and inflammatory etiologies. The probabilities were compared using the log–rank test. Time zero was defined as the first clinic visit. Survival data were censored at year 10 of follow-up, the last available clinic date, or the last clinic date prior to transfer at age 18 years. Using Cox proportional hazards regression analysis, we compared the risk of first intervention (endovascular or surgical) by etiology of vascular disease, and by extent of vascular involvement. Multivariable adjustment for potential confounders included age and sex, baseline systolic blood pressure z-score using a forward model building approach. The proportional hazards assumption was tested using the Schoenfeld residuals. To determine the association of etiology, extent of disease, and management type (intervention or medical) with the longitudinal change in systolic blood pressure z-scores, linear mixed-effects models were used (with random slope and intercept, and unstructured covariance). Potential confounders included number of antihypertensive medications and body mass index z-score. Akaike Information Criterion and likelihood ratio test was used to assess model fit. To explore an era effect, children were stratified into 2 groups based on the year of presentation (1986–2005 and 2006–2016) and characteristics were compared using a t-test. A 2-tailed P value <0.05 was considered statistically significant. All statistical analyses were performed using Stata 13.0 (College Station, TX). RESULTS Clinical characteristics at presentation A total of 93 children met the inclusion criteria and were included in the study. The study cohort had a mean age of 7.0 (SD ± 5.4) years at presentation, and 48% were male (Table 1). Most children (62%) were clinically asymptomatic at presentation. The most common findings at presentation included hypertension (60%) and a systolic murmur (30%). Mean systolic blood pressure z-score was 2.2 ± 1.8, and mean diastolic blood pressure z-score was 1.1 ± 1.5. In terms of etiology, 50% of children had disease of unknown etiology, 26% had genetic diseases, and 24% had inflammatory disease. Of those with genetic disease, 11 children had neurofibromatosis type I, 10 children had Williams Syndrome, and the remainder had Alagille Syndrome. Inflammatory disease consisted of Takayasu’s arteritis in 21 children, and nonspecific arteritis in 1 child. Children with genetic disorders presented at a younger age compared to those with unknown disease (P = 0.01), while those with inflammatory disease presented at an older age (P = 0.01). Table 1. Aortic, visceral, and extra-aortic involvement in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis type I, Williams’ Syndrome, and Alagille Syndrome. bNot specified in imaging report. cDefined as abdominal collateral vessels. View Large Table 1. Aortic, visceral, and extra-aortic involvement in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P  Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01  Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2 Renal artery disease  Renal artery 88 (94.6) 46 (97.8) 22 (91.7) 20 (90.9) 0.02   Unilateral 31 (35.2) 23 (50.0) 4 (18.2) 4 (20) 0.02   Bilateral 49 (55.7) 20 (43.5) 16 (72.7) 13 (65) –   Unspecifiedb 8 (9.1) 3 (6.5) 2 (9.1) 3 (15) –  Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4   Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4   Left 13 (14.0) 9 (56.3) 4 (100.0) – 0.05 Abdominal aortic disease  Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001   Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7   Supra-renal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) – Other aortic and visceral artery involvement  Other aortic involvement   Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02   Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01  Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002  Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01  Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) – 0.2 Extra-aortic involvement  Collateralsc 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2  Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8  Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01  Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2  Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003  Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis type I, Williams’ Syndrome, and Alagille Syndrome. bNot specified in imaging report. cDefined as abdominal collateral vessels. View Large Vascular phenotype Of the total cohort, 49% had isolated RAS, and 51% had MAS/RAS (42 had both MAS and RAS; 5 had MAS alone). Involvement of aortic and extra-aortic vessels is summarized in Table 1. Abdominal aortic disease was confined to the peri-renal region in 70% of children. There was proximal aortic involvement of the ascending aorta and aortic arch in 20% of total children, and descending thoracic involvement in 12 (13%). Almost 95% of patients had renal arterial involvement, which was bilateral in 56% of the cases. Superior mesenteric artery and celiac artery stenosis were present in 37% and 36% of children, respectively. Children with genetic or inflammatory disease had significantly more celiac and superior mesenteric artery involvement compared to the unknown etiology (46% and 64% compared to 20%, P = 0.002). Approximately 18% of children had cerebrovascular involvement including vertebral, basilar, and cerebral arteries. Carotid involvement including common, external, or internal carotid arteries was reported in 17% of children and was more prevalent in those with systemic (genetic and inflammatory) disease compared to unknown disease. Initial management and postoperative outcomes A total of 62 children received oral antihypertensive drugs upon initial presentation. The remainder of the children had systolic blood pressures less than the 95% percentile at baseline and did not require immediate antihypertensive therapy, including children with genetic diseases who were referred following screening for aortic disease. The most commonly used agents at presentation included calcium channel blockers (66%), followed by angiotensin-converting enzyme inhibitors (31%), diuretics (13%), alpha blockers (10%), and beta blockers (7%). Invasive management included surgical and endovascular procedures as summarized in Table 2. A total of 65 children (70%) received a first intervention, and 30% were managed with antihypertensive therapy alone. Children were typically managed with surgical or endovascular procedures based on nonresponse to antihypertensive therapy, escalation of antihypertensive therapy, evidence of end-organ disease, or manifestations of vascular compromise. Endovascular interventions were performed in 53 children and consisted primarily of a percutaneous transluminal angioplasty with additional stent placement in 13 children (aortic stent n = 10; renal artery n = 3). Approximately 85% of procedures were uneventful, and 13% had complications. The first follow-up visit was 9 ± 2 months following the procedure. Mean blood pressure z-score was 1.7 ± 1.6 (compared to 2.4 ± 2.0 preintervention, P = 0.7). Mean number of antihypertensive medications was 1.9 ± 1.1 (compared to 1.3 ± 1.0 preintervention, P = 0.06). Table 2. Interventional management and postoperative outcomes in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis, Williams’ Syndrome, and Alagille Syndrome. bSixty-five children had at least one intervention, including 17 children who had both a surgical and an endovascular intervention. cPTA, percutaneous transluminal angioplasty. dPostoperative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after intervention. View Large Table 2. Interventional management and postoperative outcomes in 93 children with RAS and/or MAS by underlying etiology Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Overall Unknown Genetica Inflammatory n = 93 n = 47 n = 24 n = 22 Variable Mean ± SD or n (%) P Endovascular managementb 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01  Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001  Procedure   PTAc 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002   PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6)  Postoperative outcomes   Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4   Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) –   Unsuccessful 1 (1.9) 1 (3.0) – – –  Blood pressure outcomesd   Systolic blood pressure z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4 Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8  Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003  Procedure   Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2   Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1   Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1   Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) – 0.3   Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1  Postoperative outcomes   Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4   Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) –  Blood pressure outcomesd   Systolic blood pressure z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.4   Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis. aGenetic etiology consists of Neurofibromatosis, Williams’ Syndrome, and Alagille Syndrome. bSixty-five children had at least one intervention, including 17 children who had both a surgical and an endovascular intervention. cPTA, percutaneous transluminal angioplasty. dPostoperative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after intervention. View Large Twenty-nine children (31%) had a surgery including reconstruction patch grafts, nephrectomy, and aortoaortic bypass. Postoperative course was uneventful in 69% of children. The first postoperative clinic visit was 8 ± 2 months following the procedure. Mean blood pressure z-score after surgery was 1.9 ± 1.5 (compared to 2.8 ± 2.0 before surgery, P = 0.2). Mean number of antihypertensives used was 1.9 ± 1.1 (compared to 1.2 ± 1.0 preintervention, P = 0.01). A total of 17 children had both an endovascular and a surgical procedure. Over the observation period, 2 children died of hypoxic-ischemic injury at presentation, and vessel necrosis following an aortic stent placement. The probability of receiving a first intervention differed significantly by etiology of disease (Figure 1). Children with unknown etiology had the highest cumulative probability of receiving surgical or endovascular, followed by those with inflammatory disease, and the lowest probability in those with genetic conditions (P log–rank = 0.002; Figure 1). Median time to intervention was 0.7 [0.1–1.9] years from first clinic visit in children with unknown disease, 1.7 [0.3–5.2] years in those with inflammatory disease, and 2.9 [0.8–4.7] years in those with genetic disease. After adjusting for age, sex, and systolic blood pressure z-score, children with unknown disease had a 3 times higher risk of receiving an intervention compared to those with systemic disease (hazard ratio 3.1, 95% confidence interval [CI] 1.7, 5.6) by Cox regression. Those with RAS/MAS had a 60% lower risk of receiving invasive management compared to those with isolated RAS (hazard ratio 0.4, 95% CI 0.2, 0.8) after similar adjustment. Figure 1. View largeDownload slide Interventional procedures (endovascular or surgical) among children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) of unknown, genetic, or inflammatory etiologies. Figure 1. View largeDownload slide Interventional procedures (endovascular or surgical) among children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) of unknown, genetic, or inflammatory etiologies. Follow-up Median follow-up was 1.9 [0.4–4.7] years. Figure 2 summarizes annual systolic blood pressure z-score over the longitudinal follow-up period stratified by medical management or intervention. Blood pressures remained elevated over the follow-up period in both children receiving medical management alone and those who underwent interventions, with a median blood pressure z-score of 2.0 [1.1–3.2]. Blood pressure z-score, presence of hypertension, and number of antihypertensive medications at last follow-up compared to baseline values are presented in Table 3. By linear mixed-effects analysis, the longitudinal change in systolic blood pressure Z-score was higher in those with MAS/RAS compared to those with isolated RAS (unadjusted β = 1.3, 95% CI 0.6, 1.9), even after adjustment for number of antihypertensive agents (adjusted β = 1.2, 95% CI 0.6, 1.8). The longitudinal change in systolic blood pressures did not differ by etiology, or between medical and interventional management. There were no differences in outcomes in terms of residual hypertension and use of antihypertensive medications between those receiving interventional management compared to those managed medically (Supplementary Table 1). Table 3. Blood pressures and antihypertensive therapy use in 93 children with RAS and/or MAS at clinical presentation (baseline) and last follow-up by underlying etiology, extent of disease, and management type Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis; RAS/MAS: RAS with MAS (n = 42) or MAS alone (n = 5). View Large Table 3. Blood pressures and antihypertensive therapy use in 93 children with RAS and/or MAS at clinical presentation (baseline) and last follow-up by underlying etiology, extent of disease, and management type Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Hypertension, n (%) Systolic blood pressure z-score, mean ± SD Number of antihypertensive medications, mean ± SD Variable Baseline Follow-up P Baseline Follow-up P Baseline Follow-up P  Overall cohort (n = 93) 56 (60.2) 61 (65.6) 0.3 2.2 ± 1.8 2.4 ± 1.6 0.6 1.2 ± 1.1 1.2 ± 1.0 0.5 Etiology  Unknown (n = 47) 25 (53.2) 25 (53.2) 0.7 2.0 ± 1.6 2.2 ± 1.6 0.5 1.2 ± 1.0 1.2 ± 1.0 0.6  Genetic (n = 24) 15 (62.5) 20 (83.3) 0.2 2.2 ± 2.0 2.5 ± 1.7 0.3 1.2 ± 1.0 1.1 ± 1.0 0.5  Inflammatory (n = 22) 13 (59.1) 16 (72.7) 0.9 2.1 ± 1.7 2.4 ± 1.7 0.7 1.3 ± 1.1 1.2 ± 1.1 0.4 Extent of disease  Isolated RAS (n = 46) 24 (52.2) 25 (54.4) 0.8 1.8 ± 1.6 2.1 ± 1.6 0.8 0.9 ± 0.8 1.0 ± 0.9 0.6  RAS/MAS (n = 47) 29 (61.7) 36 (76.6) 0.1 2.4 ± 1.8 2.6 ± 1.7 0.7 1.4 ± 1.2 1.4 ± 1.3 0.4 Management  Invasive (n = 65) 41 (63.1) 42 (64.6) 0.6 2.3 ± 1.9 2.4 ± 1.7 0.4 1.1 ± 1.0 1.1 ± 1.1 0.4  Medical (n = 28) 12 (42.9) 19 (67.9) 0.03 1.6 ± 1.4 2.2 ± 1.4 0.06 1.1 ± 1.1 1.2 ± 1.1 0.7 Abbreviations: MAS, middle aortic syndrome; RAS, renal artery stenosis; RAS/MAS: RAS with MAS (n = 42) or MAS alone (n = 5). View Large Figure 2. View largeDownload slide Systolic blood pressure z-score at annual follow-up over the study period in children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) receiving medical management (antihypertensive therapy) and interventional management (endovascular and surgical interventions). Figure 2. View largeDownload slide Systolic blood pressure z-score at annual follow-up over the study period in children with renal artery stenosis (RAS) and/or middle aortic syndrome (MAS) receiving medical management (antihypertensive therapy) and interventional management (endovascular and surgical interventions). Approximately 66% of children were still hypertensive at follow-up, with a mean systolic blood pressure z-score of 2.4 ± 1.6 (Table 3). Approximately 17% were normotensive without requiring any antihypertensive medications, and 17% had controlled blood pressure with antihypertensive therapy. Mean number of antihypertensive agents used was 1.2 ± 1.0 (compared to 1.9 ± 1.0 immediately post-intervention, P = 0.03), and did not differ by etiology or by extent of vascular disease. Of those who received a primary endovascular or surgical intervention, 33 (51%) had a re-stenosis of the same vessel (following a first endovascular intervention), and 25 (39%) required a re-intervention. Re-interventions were more common among those with genetic and inflammatory disease compared to children with unknown disease (58% and 69% vs. 23%, respectively, P < 0.001). There was no progression from isolated RAS to MAS/RAS and no additional aortic branch involvement. Era effect The majority of children diagnosed with RAS and/or MAS presented in the last 10 years of the study period (Supplementary Figure 1). Supplementary Table 2 compares the characteristics of children presenting during the first (1986–2005, n = 41) and second (2006–2016, n = 52) periods of the reported experience. Children in the earlier period presented at a younger age (6 ± 5 vs. 8 ± 6, respectively, P = 0.04). The earlier time period had a higher proportion of children undergoing surgical intervention and a higher proportion of re-interventions. DISCUSSION In a comprehensive review of childhood RAS and/or MAS, our results demonstrate that even after conservative medical or interventional management, more than two thirds of children have persistent hypertension requiring long-term antihypertensive management. Most children with RAS and/or MAS undergo endovascular or surgical interventions to control blood pressure, with longer periods of time prior to intervention in children with genetic and inflammatory diseases than those with no known etiology. The majority of children have no known cause of disease, with the extent of vessel involvement relatively confined to the peri-renal aorta. Children with genetic and inflammatory disease have additional vascular involvement including visceral and proximal aortic branches. Despite the increased recognition of the clinical presentation of RAS and MAS in children over the past decade, there are many gaps in our understanding of this disease. One of the main challenges in managing RAS and MAS is the unknown pathogenesis of the vascular disease. This is crucial given that etiology of disease greatly influences the choice and timing of interventional management in children. Interventions are often delayed during the acute phase of inflammatory diseases, and in children with genetic causes given the potential risk associated with invasive management, and concern of potential progression due to the underlying vasculopathy. A diagnosis of exclusion often attributed to RAS and MAS is fibromuscular dysplasia.19 In most reported series of childhood RAS, there is little evidence of the classic angiographic appearance of beading, a common feature of medial fibroplasia in adults.20 The vascular involvement in adult fibromuscular dysplasia compared to pediatric cases of RAS/MAS is clearly different, with more cerebrovascular and carotid disease in adults compared to isolated RAS or confined peri-renal aortic disease in children,1,21,22 consistent with the findings in our cohort. In a systematic review of childhood MAS, we demonstrated that aortic involvement is predominantly confined to the peri-renal segment of the aorta, with a high propensity for bilateral RAS.1 Our current study corroborates the anatomical classification based on the systematic review, as there are cases of isolated RAS but almost all MAS cases include RAS. Importantly, we found no evidence of vascular disease progression in terms of new aortic involvement or expanding vascular involvement of other abdominal vessels. Similar to other studies, we observed re-stenosis of vessels following endovascular intervention,21–25 which was often confined to the same treated vessel. It is worth noting, however, that we did not conduct systematic imaging of nondiseased vessels such as the carotid arteries. Future studies should confirm these findings with more systematic vascular imaging on follow-up. An important finding is the persistent hypertension in children with renovascular disease following endovascular and surgical management. Given that the majority of children still require antihypertensive management despite partial or complete relief of arterial narrowing,1,3 defining treatment success as complete resolution of hypertension may not be realistic in children with RAS and/or MAS. In contrast to other studies that report complete resolution of hypertension in children,14,26 we found that over two thirds of children had persistent hypertension for a median of 2 years after the initial procedure. These differences may be due to the greater heterogeneity of the vascular involvement, as well as the higher proportion of systemic diseases in our cohort compared to other studies. Only 18% of children in our cohort had complete normalization of blood pressure without any need for medications. Similar proportions are reported in other series of childhood RAS and MAS.3,26 The etiology of the persistent hypertension remains unclear, with hypotheses that include an underlying arteriopathy, or an effect of residual narrowing on proximal hemodynamics.27–30 In contrast to published case series from other centers, diagnostic angiography and follow-up catheter-based imaging are not routinely performed in our pediatric cohort.26 Rather, follow-up imaging mainly consists of abdominal ultrasound until worsening of symptoms or evidence of end-organ disease merit further cross-sectional imaging (computed tomography angiography or magnetic resonance angiography) or a secondary intervention. Clear guidelines for the diagnosis and management of renovascular hypertension in children are not defined and are challenging to standardize given the heterogeneity of this population in terms of etiology, response to medications, and vascular involvement. Previous studies have advocated residual hypertension with 2 or more antihypertensive agents as criteria for endovascular intervention,26 however, the potential benefit of blood pressure lowering with angioplasty needs to be balanced against the associated risk of repeated interventions especially given the high prevalence of persistent hypertension even after a successful endovascular procedure. This study has some limitations inherent to its retrospective design. Children underwent variable imaging modalities and of different vascular beds, which may have limited the extent of phenotypic description. Additionally, our experience spans 30 years during which temporal trends may have occurred in antihypertensive management and indications for endovascular or surgical intervention, as well as clinical follow-up. Given the anatomic variability and variation in the degree of extra-aortic involvement, surgical management often needs to be individualized. Antihypertensive management is also not standardized and may vary by prescribing physician, but statistical adjustment for number of medications was undertaken. Although there was no improvement in systolic blood pressures over 2 years of follow-up, there may have been changes in end-organ disease, symptoms, and quality of life. Medical or invasive management can have benefit in these areas that this study was not able to capture. Further, manual blood pressure measurements were not consistently reported in clinical records, thus lacking precision. However, repeated measures in individuals were used to ascertain elevated blood pressure. Lastly, as our median follow up is 2 years, we are not able to comment on long-term outcomes in this population. Despite these limitations, our results demonstrate important clinical observations from one of the largest cohorts of childhood RAS and MAS and emphasize the need for close monitoring of this high-risk group. Our cohort has a number of strengths in that all children with MAS and/or RAS were included regardless of etiology. Further, the study highlights the differences in the time to intervention by etiology. This may have clinical implications as intervention with genetic disorders could be considered sooner given that progression of vascular disease was not common. Additionally, longitudinal analysis of repeated blood pressure measurements demonstrated persistent hypertension even after successful interventional management. Further studies are needed to evaluate the effect of this persistent hypertension on end-organ cardiac disease. CONCLUSION RAS and/or MAS, often coexisting, are important causes of hypertension in children. The vascular involvement is localized to the peri-renal aorta, and the majority of cases have no known etiology. Children with inflammatory and genetic diseases and those with more extensive vascular involvement are less likely to have endovascular or surgical interventions. We found that residual hypertension persists in more than two thirds of children after both medical and interventional therapy. Our findings highlight the importance of blood pressure control and need for close monitoring of children with RAS and/or MAS even after interventions. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. ACKNOWLEDGMENT This study was supported by the Banting & Best Scholarship from the Canadian Institute for Health Research (CGS-M) (http://www.cihr-irsc.gc.ca) through the Frederick Banting and Charles Best Canada Graduate Scholarship. REFERENCES 1. Rumman RK , Nickel C , Matsuda-Abedini M , Lorenzo AJ , Langlois V , Radhakrishnan S , Amaral J , Mertens L , Parekh RS . Disease beyond the arch: a systematic review of middle aortic syndrome in childhood . Am J Hypertens 2015 ; 28 : 833 – 846 . Google Scholar CrossRef Search ADS PubMed 2. Delis KT , Gloviczki P . Middle aortic syndrome: from presentation to contemporary open surgical and endovascular treatment . Perspect Vasc Surg Endovasc Ther 2005 ; 17 : 187 – 203 . Google Scholar CrossRef Search ADS PubMed 3. Porras D , Stein DR , Ferguson MA , Chaudry G , Alomari A , Vakili K , Fishman SJ , Lock JE , Kim HB . Midaortic syndrome: 30 years of experience with medical, endovascular and surgical management . Pediatr Nephrol 2013 ; 28 : 2023 – 2033 . Google Scholar CrossRef Search ADS PubMed 4. Connolly JE , Wilson SE , Lawrence PL , Fujitani RM . Middle aortic syndrome: distal thoracic and abdominal coarctation, a disorder with multiple etiologies . J Am Coll Surg 2002 ; 194 : 774 – 781 . Google Scholar CrossRef Search ADS PubMed 5. Sethna CB , Kaplan BS , Cahill AM , Velazquez OC , Meyers KE . 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Google Scholar CrossRef Search ADS PubMed © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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American Journal of HypertensionOxford University Press

Published: Jan 24, 2018

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