Surgical management of pediatric renin-mediated hypertension secondary to renal artery occlusive disease and abdominal aortic coarctation

Published:April 07, 2020DOI:https://doi.org/10.1016/j.jvs.2020.02.045

      Abstract

      Background

      Renovascular hypertension (RVH) associated with renal artery and abdominal aortic narrowings is the third most common cause of pediatric hypertension. Untreated children may experience major cardiopulmonary complications, stroke, renal failure, and death. The impetus of this study was to describe the increasingly complex surgical practice for such patients with an emphasis on anatomic phenotype and contemporary outcomes after surgical management as a means of identifying those factors responsible for persistent or recurrent hypertension necessitating reoperation.

      Methods

      A retrospective analysis was performed of consecutive pediatric patients with RVH undergoing open surgical procedures at the University of Michigan from 1991 to 2017. Anatomic phenotype and patient risk factors were analyzed to predict outcomes of blood pressure control and the need for secondary operations using ordered and binomial logistic multinomial regression models, respectively.

      Results

      There were 169 children (76 girls, 93 boys) who underwent primary index operations at a median age of 8.3 years; 31 children (18%) had neurofibromatosis type 1, 76 (45%) had abdominal aortic coarctations, and 28 (17%) had a single functioning kidney. Before treatment at the University of Michigan, 51 children experienced failed previous open operations (15) or endovascular interventions (36) for RVH at other institutions. Primary surgical interventions (342) included main renal artery (136) and segmental renal artery (10) aortic reimplantation, renal artery bypass (55), segmental renal artery embolization (10), renal artery patch angioplasty (8), resection with reanastomosis (4), and partial or total nephrectomy (25). Non-renal artery procedures included patch aortoplasty (32), aortoaortic bypass (32), and splanchnic arterial revascularization (30). Nine patients required reoperation in the early postoperative period. During a mean follow-up of 49 months, secondary interventions were required in 35 children (21%), including both open surgical (37) and endovascular (14) interventions. Remedial intervention to preserve primary renal artery patency or a nephrectomy if such was impossible was required in 22 children (13%). The remaining secondary procedures were performed to treat previously untreated disease that became clinically evident during follow-up. Age at operation and abdominal aortic coarctation were independent predictors for reoperation. The overall experience revealed hypertension to be cured in 74 children (44%), improved in 78 (46%), and unchanged in 17 (10%). Children undergoing remedial operations were less likely (33%) to be cured of hypertension. There was no perioperative death or renal insufficiency requiring dialysis after either primary or secondary interventions.

      Conclusions

      Contemporary surgical treatment of pediatric RVH provides a sustainable overall benefit to 90% of children. Interventions in the very young (<3 years) and concurrent abdominal aortic coarctation increase the likelihood of reoperation. Patients undergoing remedial surgery after earlier operative failures are less likely to be cured of hypertension. Judicious postoperative surveillance is imperative in children surgically treated for RVH.

      Graphical abstract

      Keywords

      Article Highlights
      • Type of Research: Single-center, retrospective analysis of prospectively collected data
      • Key Findings: Surgical revascularization of 169 children with renovascular hypertension resulted in a sustainable overall benefit in hypertension in 90% of children. Interventions in the very young and in those with concurrent abdominal aortic coarctation increase the likelihood of reoperation. Patients undergoing remedial surgery after earlier operative failures are less likely to be cured of hypertension.
      • Take Home Message: Surgical revascularization of pediatric renovascular hypertension provides a sustainable benefit in most children, including those with abdominal aortic coarctation, with no mortality or renal insufficiency requiring dialysis.
      CME Activity
      Purpose or Statement of Need The purpose of this journal-based CME activity is to enhance the vascular specialist’s ability to diagnose and care for patients with the entire spectrum of circulatory disease through a comprehensive review of contemporary vascular surgical and endovascular literature.
      Learning Objective
      • Understand the variations in anatomy in pediatric patients with renovascular hypertension and the optimal treatment, based on anatomy
      Target Audience This activity is designed for vascular surgeons and individuals in related specialties.
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      Pediatric renovascular hypertension (RVH) secondary to renal artery occlusive lesions and abdominal aortic coarctations risks significant morbidity and mortality.
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      ,
      • Silverstein D.M.
      • Champoux E.
      • Aviles D.H.
      • Vehaskari V.M.
      Treatment of primary and secondary hypertension in children.
      The pathophysiology and etiology of both diseases remain poorly defined. Moreover, the low frequency of these entities limits existing data to institutional series and anecdotal case reports. The optimal management of these children, including indications for invasive treatment, remains ill-defined. To date, there are no randomized trials comparing medical management with surgical revascularization for pediatric RVH.
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      ,
      • Rumman R.K.
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      • Langlois V.
      • Radhakrishnan S.
      • Lorenzo A.J.
      • Amaral J.
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      Management and outcomes of childhood renal artery stenosis and middle aortic syndrome.
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      • et al.
      Long-term outcomes of pediatric renovascular hypertension.
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      Interventions for pediatric renovascular hypertension.
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      • et al.
      Interventions in children with renovascular hypertension: a 27-year retrospective single-center experience.
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      • et al.
      The management of pediatric renovascular hypertension: a single center experience and review of the literature.
      • Kim H.B.
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      • Ramos-Gonzalez G.J.
      • Stein D.R.
      • Ferguson M.A.
      • Porras D.
      • et al.
      Tissue expander-stimulated lengthening of arteries for the treatment of midaortic syndrome in children.
      Moreover, the role of endovascular interventions as a first-line or “bridging” option for treatment of pediatric RVH has not been defined.
      • Tullus K.
      • Brennan E.
      • Hamilton G.
      • Lord R.
      • McLaren C.A.
      • Marks S.D.
      • et al.
      Renovascular hypertension in children.
      • Zhu G.
      • He F.
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      • Chen B.
      • Hu Z.
      • et al.
      Angioplasty for pediatric renovascular hypertension: a 13-year experience.
      • Alexander A.
      • Richmond L.
      • Geary D.
      • Salle J.L.
      • Amaral J.
      • Connolly B.
      Outcomes of percutaneous transluminal angioplasty for pediatric renovascular hypertension.
      • Srinivasan A.
      • Krishnamurthy G.
      • Fontalvo-Herazo L.
      • Nijs E.
      • Keller M.S.
      • Meyers K.
      • et al.
      Angioplasty for renal artery stenosis in pediatric patients: an 11-year retrospective experience.
      • Shroff R.
      • Roebuck D.J.
      • Gordon I.
      • Davies R.
      • Stephens S.
      • Marks S.
      • et al.
      Angioplasty for renovascular hypertension in children: 20-year experience.
      A previous report from the University of Michigan on the surgical treatment of 97 children having RVH demonstrated a 97% benefit for blood pressure control.
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      The authors' surgical experience has nearly doubled since 2005 and has become increasingly complicated in that prior open surgical or endovascular failures now account for a third of those referred for definitive care. The impetus of this study was to describe the increasingly complex surgical care of such patients with an emphasis on anatomic phenotype and contemporary outcomes after their surgical management as a means of identifying those factors responsible for persistent or recurrent hypertension necessitating reoperation.

      Methods

      The medical records of consecutive children, 18 years or younger, with RVH undergoing surgical procedures at the University of Michigan from 1991 to 2017 were reviewed. Children operated on before 1991 were excluded because of many instances of limited follow-up. Currently, all data of interventions for pediatric renovascular disease treated at the University of Michigan are prospectively entered into an institutional registry. This series included 50 children (of the aforementioned 97) who have been previously described, specifically treated after 1991 with complete records,
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      and 119 more recent and heretofore unreported cases.
      Refractory hypertension unresponsive to optimal drug therapy was the basis for surgical intervention in all but one patient. For reference, normal blood pressure in a pediatric patient exists when it is <90th percentile for sex, age, and height. Hypertension is defined as an average systolic or diastolic blood pressure ≥95th percentile for sex, age, and height across three separate measurements and is categorized using published standards of pediatric blood pressure.
      • Flynn J.T.
      • Kaelber D.C.
      • Baker-Smith C.M.
      • Blowey D.
      • Carroll A.E.
      • Daniels S.R.
      • et al.
      Clinical practice guideline for screening and management of high blood pressure in children and adolescents.
      Postoperatively, hypertension outcomes were classified as cured if children were normotensive, requiring no antihypertensive medications at the time of last follow-up; improved if their blood pressures were within normotensive ranges while receiving a less intensive antihypertensive regimen; and therapeutic failures if their diastolic pressures were higher than the normal levels and not 15% lower than preoperative levels or if angiotensin-converting enzyme inhibitors were required for blood pressure control. This retrospective review was approved by the Institutional Review Board at the University of Michigan (HUM0006223), and a waiver of informed consent was granted.
      The association of each independent variable (age, aortic reconstruction, neurofibromatosis type 1 [NF1], abdominal aortic coarctation, prior renal artery intervention, and number of antihypertensive medications) with the occurrence of a reoperation was estimated using bivariate logistic regression. This was followed by a multiple logistic regression to estimate the effect of the independent variable on the odds of undergoing a reoperation. Pairwise comparison of marginal effects was used to see whether the probability of reoperation differed by the type of aortic reconstruction. The variable change in medications before intervention to after intervention was modeled using simple ordinal logistic regression to estimate the effect of each independent variable. This was followed by a multiple ordinal logistic regression to estimate the effect of each independent variable. Kaplan-Meier survival curves were used to estimate the potential for reoperation along with a log-rank test to detect whether such potential differed significantly if associated with an aortic coarctation reconstruction, a prior renal artery procedure, or the presence of NF1. Cox proportional hazards modeling was used to assess the impact of age and initial number of medications on the potential for reoperation. All statistical analyses were done using Stata version 15.1 software (StataCorp LLC, College Station, Tex). Statistical significance was defined as P < .05.

      Results

      A total of 169 children with RVH were treated surgically at the University of Michigan from 1991 to 2017 (Table I). This surgical cohort demonstrated a slight male predominance (n = 93 [55%]). The median age of children at the time their hypertension was recognized was 5 years (standard deviation [SD], ± 60 months). The median age at the time of their primary operation at the University of Michigan was 8.2 years (SD, ± 63 months; range, 3 months-18 years), and the median weight was 24.95 kg (SD, ± 20 kg; range, 5.2-97.6 kg). Prior interventions for RVH had been performed in 51 (30%) of the series' children at other institutions before they were referred to and received treatment at the University of Michigan.
      Table IDemographics and preoperative risk factors
      VariableTotal cohort (N = 169)
      Male sex93 (55)
      Age at time of surgical intervention at University of Michigan, years8.96 ± 5.53
      Weight at time of intervention at University of Michigan, kg58.33 ± 16.8
      No. of initial antihypertensive medications2.70 ± 1.58
      NF131 (18.34)
      Abdominal aortic coarctation76 (44.97)
      Prior intervention performed elsewhere for RVH before intervention at University of Michigan51 (30.18); open surgical (14), endovascular (35), combination (2)
      NF1, Neurofibromatosis type 1; RVH, renin-mediated renovascular hypertension.
      Categorical variables are presented as number (%). Continuous variables are presented as mean ± standard deviation.

       Historical risk factors

      NF1 affected 31 (18%) of the series' children. Additional concurrent diagnoses included Williams syndrome (6), scoliosis (5), moyamoya disease (5), Klippel-Trénaunay syndrome (1), Beals syndrome (1), von Willebrand disease (1), Takayasu arteritis (1), Noonan syndrome (1), gonadal dysgenesis (1), Alagille syndrome (1), macrocephaly (1), monosomy 16p (1), trisomy 21q (1), and alpha thalassemia (1).
      Five patients had a neoplastic disease, including a single yolk sac tumor (1), Wilms tumor (1), hemangioendothelioma (1), neuroblastoma (1), and retroperitoneal neurofibroma (1). Hypertension was incidentally diagnosed in 90 asymptomatic children. The remaining 79 children were symptomatic, of which headache was the most common manifestation (Table II). Eighteen patients were younger than 3 years at the time of their primary operation at the University of Michigan. In this subgroup of the very young, both malignant hypertension (n = 5 [28%]) and failure to thrive (n = 4 [22%]) were relatively common. In contrast, these manifestations in children older than 3 years were less common (n = 4 [5%]). The mean number of antihypertensive medications preoperatively was 2.70 (SD, ± 1.58). Mean creatinine concentration preoperatively was 0.62 mg/dL (SD, ± 0.31 mg/dL). Among children having preoperative echocardiography, 68% (69) exhibited left ventricular hypertrophy.
      Table IIClinical manifestations
      Symptom or sign(N = 79 [53% of total cohort])
      Headache25
      Failure to thrive11
      Malignant hypertension (including hypertensive encephalopathy)13
      Lower extremity symptoms (claudication, leg fatigue with walking)
      All cases associated with abdominal aortic coarctations.
      11
      Neurologic events or symptoms
       Stroke6
       Stroke with moyamoya4
       Seizure
      Exclusive of diagnosed seizure disorder.
      3
      Abdominal symptoms (pain, nausea, recurrent emesis)9
      Epistaxis6
      Facial nerve palsy4
      Visual change (including hypertensive retinopathy)4
      Agitation, irritability3
      Hematuria (including microscopic)3
      Dyspnea on exertion2
      a All cases associated with abdominal aortic coarctations.
      b Exclusive of diagnosed seizure disorder.

       Vascular anatomy

      Renal artery lesions were often bilateral (n = 91 [54%]), being frequently ostial (n = 112 [66%]) in most cases (Fig 1; Table III). Multiple renal arteries occurred in 21% of patients (36). Twenty-eight children (17%) had a single functioning kidney at the time of the primary operation related to ischemic atrophy (12), prior nephrectomy (13), or congenital absence (3). Nearly half the children (83) had splanchnic artery stenoses or occlusions affecting the celiac artery, superior mesenteric artery, or both. Four individuals had evidence of diffuse arterial dysplasia with “beading” of the ileocolic (1), hepatic (4), and splenic (2) arteries. Almost half the children (76) had a concurrent abdominal aortic coarctation (Fig 2, Fig 3, Fig 4); six had a concurrent thoracic isthmic aortic coarctation, and one had a bicuspid aortic valve. Concurrent abdominal (large-vessel) arterial aneurysms affected the aorta (2), common iliac artery (1), hypogastric artery (1), renal artery (9), inferior mesenteric artery (1), or ureteric collateral artery (1).
      Figure thumbnail gr1
      Fig 1A, Preoperative arteriogram of an 8-year-old boy with medically refractory renovascular hypertension (RVH) and bilateral renal artery ostial stenosis. B, Postoperative completion arteriogram after bilateral renal artery reimplantation.
      Table IIIRenal vascular anatomy and associated disease
      Renal artery anatomyEntire cohort (N = 169)Absence of abdominal aortic coarctation (n = 93 [55% of total cohort])Abdominal aortic coarctation (n = 76 [45% of total cohort])Presence of NF1 (n = 31 [18% of total cohort])Absence of NF1 (n = 138 [82% of total cohort])
      Bilateral stenoses91 (54)35 (38)56 (74)18 (58)73 (53)
      Multiple renal arteries36 (21)19 (20)17 (22)4 (13)32 (23)
      Ostial stenosis112 (66)52 (56)60 (79)28 (90)84 (61)
      Mid-renal artery stenosis14 (8)1 (1)13 (17)014 (10)
      Distal artery stenosis6 (4)6 (6)01 (3)5 (4)
      Segmental arterial stenosis17 (10)13 (14)4 (5)2 (6)15 (11)
      Diffuse renal artery dysplasia59 (3)3 (3)2 (3)1 (3)4 (3)
      Focal renal artery occlusion26 (15)17 (18)9 (12)3 (10)23 (17)
      NF1, Neurofibromatosis type 1.
      Values are reported as number (%).
      Figure thumbnail gr2
      Fig 2A, Preoperative computed tomography arteriogram of a 7-year-old boy with a single right kidney and medically refractory renovascular hypertension (RVH) demonstrating suprarenal abdominal aortic coarctation with ostial stenosis of the two right renal arteries and the superior mesenteric artery. B, Postoperative completion arteriogram after aortoaortic bypass with superior mesenteric artery intimectomy and reimplantation of the right superior and inferior renal arteries onto the transected aorta (arrow). He remains cured of hypertension now 9 years out from surgical revascularization.
      Figure thumbnail gr3
      Fig 3A, Preoperative arteriogram of a 15-year-old boy with medically refractory renovascular hypertension (RVH) and lower extremity exertional fatigue demonstrating partial duplication of the aorta and abdominal aortic coarctation with bilateral ostial renal artery stenoses. B, Postoperative completion computed tomography arteriogram after aortoaortic bypass using 16-mm expanded polytetrafluoroethylene (ePTFE) graft, ligation and division of dysplastic and narrowed aorta distal to the superior mesenteric artery, and bilateral renal artery reimplantation onto the transected terminal aorta.
      Figure thumbnail gr4
      Fig 4A, Preoperative arteriogram of a 6-year-old boy with medically refractory renovascular hypertension (RVH) demonstrating inter-renal abdominal aortic coarctation and bilateral ostial renal artery stenoses. B, Postoperative surveillance magnetic resonance angiogram after patch aortoplasty and bilateral renal artery reimplantation. He remains cured of hypertension >20 years out from surgical revascularization.

       Primary interventions

      A total of 342 primary surgical interventions were performed: 248 directed to renal artery occlusive disease, 64 to aortic narrowings, and 30 to occlusive lesions of the splanchnic arteries (Table IV). Renal artery reimplantation onto the aorta was performed most commonly (136 [55% of primary renal artery procedures]; Fig 1, B), followed by aortorenal bypass (50 [20% of primary renal artery procedures]). The hypogastric artery was used for conduit in 89% of the renal artery bypasses and patch angioplasties. Saphenous vein, splenic artery, common iliac artery, and expanded polytetrafluoroethylene (ePTFE) grafts were uncommonly used in these procedures. Partial (21) or complete (4) nephrectomy was performed in 12% and 2%, respectively, in children having irreparable renal atrophy (nonfunctional) or renal artery disease deemed technically unreconstructible (ie, diffuse, segmental arterial dysplasia or absent distal target for revascularization during intraoperative exploration). An additional 12 nephrectomies were performed for the 12 nonfunctional atrophic kidneys. Among the series' 76 patients with abdominal aortic coarctations, 64 required concurrent aortic surgery with an aortoaortic bypass (32; Fig 2, B, and Fig 3, B) or patch aortoplasty (32; Fig 4, B). The preferred conduit in these reconstructions was ePTFE. Concurrent splanchnic revascularizations were performed in 17% of the series' patients.
      Table IVPrimary surgical interventions at University of Michigan
      Intervention siteNo. of proceduresNotes
      Renal arteryRenal reimplantation: aortic (134), SMA (2), segmental renal artery (10)
      Renal bypass: aortorenal (50),
      A single case complicated by multilobed aneurysm required ex vivo reconstruction.
      iliorenal (2), splenorenal (1), interposition renorenal (2)
      Conduit hypogastric artery, with exception of GSV (2), ePTFE (2), CIA (1)
      Renal artery patch angioplasty (8)Conduit hypogastric artery, with exception of GSV (1), splenic artery (1)
      Resection with reanastomosis (4)
      Absolute alcohol embolization (10)
      KidneyPartial nephrectomy (4), total nephrectomy (21)
      Aorta (n = 64 [38% of cohort])Patch aortoplasty (32), aortic bypass (32)
      Ascending aortic inflow in four cases.
      Preferred conduit ePTFE
      Splanchnic arteries (n = 28 [17% of cohort])SMA intervention: hepato-SMA bypass (2), aorta-SMA bypass (3), SMA reimplantation (15), SMA ligation (2), SMA patch angioplasty by celiac reimplantation onto SMA (2), SMA intimectomy (2)Preferred conduit hypogastric artery
      Celiac artery intervention: aneurysm resection with hepatosplenic anastomosis (1), reimplantation (3)
      CIA, Common iliac artery; ePTFE, expanded polytetrafluoroethylene; GSV, great saphenous vein; SMA, superior mesenteric artery.
      a A single case complicated by multilobed aneurysm required ex vivo reconstruction.
      b Ascending aortic inflow in four cases.
      Length of stay after these primary procedures averaged 13.6 days (SD, ± 9.1 days). Surgical morbidity was not life-threatening but relevant (Table V). Nine patients (5%) required reoperation in the early postoperative period (within 30 days) primarily related to graft thrombosis or bleeding. Chemical pancreatitis with or without an accompanying ileus was the most common complication affecting 20 patients (12%), followed by infections (7%) unrelated to aortic or arterial reconstruction, and pulmonary complications (7%). Renal insufficiency requiring dialysis during the study period did not occur, and there were no cases of infection involving the site of the renal, aortic, or splanchnic arterial procedures. There was no death during this study period.
      Table VPerioperative complications
      SystemComplication
      ReoperationRenal graft thrombosis requiring nephrectomy (2) and revision (1), postoperative hemorrhage (4), fascial dehiscence (1), delayed abdominal closure (1)
      Infectious (no cases of graft infection or wound infection)Bacteremia (2), UTI (4), Clostridium difficile colitis (3), vaginal yeast infection (1), thrush (1), cellulitis associated with peripheral intravenous line (1)
      GastrointestinalChemical pancreatitis or prolonged (>7 days) ileus (20), gastrointestinal bleed (2)
      RespiratoryPneumonia (7, of which 3 patients required prolonged intubation or reintubation), ARDS with prolonged intubation (1), viral URI (1), pneumothorax requiring tube thoracostomy (1), pleural effusion requiring tube thoracostomy (1)
      HematologicPerinephric hematoma requiring transfusion (2), phlebitis (3), DVT (2), PE (1), digital thromboembolism (1), HIT (1)
      MiscellaneousPartial-thickness skin loss (1), decubitus ulcer (1), MCA stroke (1), chylous ascites requiring delayed thoracic duct ligation (1), intraoperative splenic laceration requiring splenectomy (1)
      ARDS, Acute respiratory distress syndrome; DVT, deep venous thrombosis; HIT, heparin-induced thrombocytopenia; MCA, middle cerebral artery; PE, pulmonary embolism; URI, upper respiratory infection; UTI, urinary tract infection.

       Secondary interventions

      During a mean follow-up of 49 months, 35 children (21%) required at least one reoperation, including both open surgical (37) and endovascular (14) procedures directed at the renal arteries (36) or aorta (15) and fewer directed at the splanchnic arteries (Table VI). The relative incidence of reoperation was higher in patients with concurrent abdominal aortic narrowings (n = 19 [24%]) and NF1 (n = 9 [29%)]. Secondary intervention to preserve primary patency or a nephrectomy if such was impossible was required after index operation in 22 children (13% of total cohort); the remaining subsequent operations were not “reoperation” but rather required to treat evolving aortic, renal, or mesenteric vascular bed that became clinically evident after the index operation. Among the 64 patients undergoing concurrent aortic operations at the time of their primary operation, 12.5% (4/32) of those having a patch aortoplasty required reoperation, and 18.8% (6/32) of those with a prior aortic bypass required reoperation. Specifically, three patients in each of these cohorts required the secondary intervention to preserve aortic patency (9%). Follow-up into adulthood was available for 38 patients, with the oldest patient being 34 years at the date of last follow-up. There were no adult complications identified or reinterventions required after age 18 years.
      Table VISecondary surgical interventions at University of Michigan
      Open surgical interventionsEndovascular interventions
      Remedial interventions for failure of primary procedure at University of MichiganRemedial renal revascularization

       Renal bypass: aortorenal (8), splenorenal (1), iliorenal (2)

      Renal reimplantation: aortic (2), SMA (1), renal artery patch angioplasty (2), renal thromboendarterectomy (2), renal intimectomy (1)

      Nephrectomy (3)

      Remedial aortic revascularization

      Aortic bypass: aortoaortic (2), aortoiliac (1), thoracoabdominal aortic bypass (2)

      Patch aortoplasty (3)

      Remedial mesenteric revascularization

      Mesenteric bypass: SMA-hepatic artery bypass (1), aorta-SMA bypass (1), aorta-celiac bypass (to address inflow to splenorenal bypass) (1)

      SMA reimplantation (2), splenic artery reimplantation (to address inflow to splenorenal bypass) (1)
      Renal/anastomotic angioplasty (9)

      Renal artery stenting (2)

      Segmental renal angioplasty (1)

      Segmental renal artery embolization (1)

      Thrombolysis of thrombosed aortorenal bypass (1)

      Aortic balloon angioplasty (2)

      Aortic stenting (4)
      Secondary interventions for disease progression unrelated to primary operationRenal reimplantation (contralateral to index renal revascularization) (4)

      Segmental renal artery reimplantation (1) Segmental renal artery embolization (1) SMA reimplantation (2)

      Aortic patch angioplasty (6)

      Thoracoabdominal aortic bypass (2)
      Renal angioplasty (1)

      Segmental embolization (3)
      SMA, Superior mesenteric artery.
      Median time to the first secondary operation in the entire series was 14 months (range, 2-159 months; SD, ± 38.43 months). Seventeen children (10%) required at least two reoperations including both open surgical (9) and endovascular (8) procedures, of whom seven needed a third open operation. One child, initially operated on at 5 years of age, required 10 additional procedures during the next 14 years, including open (5) and endovascular (5) interventions. There were no cases of late renal failure requiring renal replacement therapy and no operative mortality after any reoperation.
      Logistic regression modeling identified younger age at operation (adjusted odds ratio [OR], 0.86; 95% confidence interval [CI], 0.77-0.95) and abdominal aortic coarctation (adjusted OR, 6.01; 95% CI, 1.70-21.24) to be independent predictors of reoperation (Supplementary Table I, online only). The pairwise comparison of the effects of aortic bypass and patch on the probability of reoperation was not statistically significant. Log-rank tests documented that the hazards of reoperation did not differ significantly in relation to abdominal aortic coarctation, aortic reconstruction, NF1, or preoperative intervention (Fig 5). Age at operation significantly affected hazards of a reoperation. Specifically, as age increased by 1 year, the rate of reoperation decreased by about 10% (hazard ratio, 0.90; 95% CI, 0.83-0.97).
      Figure thumbnail gr5
      Fig 5Kaplan-Meier curve (survival analysis). Log-rank tests documented that the hazards of reoperation did not differ significantly in relation to (A) abdominal aortic coarctation (MAS), (B) concurrent aortic reconstruction (reconst), (C) neurofibromatosis type 1 (NF), and (D) preoperative intervention.
      Among the series' 169 patients, 74 (44%) were cured of hypertension, 78 (46%) were improved, and 17 (10%) were unchanged with regard to their hypertension (Table VII). Overall, the mean number of antihypertensive medications at follow-up was 0.99 ± 1.16 compared with a preoperative number of 2.7 ± 0.58. NF1 was identified by univariate analysis to be negatively associated with hypertension benefit (OR, 0.42; 95% CI, 0.2-0.91). Multiple ordinal regression modeling identified prior intervention (adjusted odds OR, 0.49; 95% CI, 0.25-0.98) as the single independent factor predicting that children undergoing remedial operations were less likely to be cured (33%) of their hypertension (Supplementary Table II, online only).
      Table VIIPostoperative hypertension benefits
      CureImprovedFailure (unchanged)
      Total cohort (N = 169)
      Includes primary index and secondary operations.
      74 (44)78 (46)17 (10)
      Among patients with concurrent abdominal aortic coarctation (n = 76)28 (37)37 (49)11 (14)
      Among patients without abdominal aortic coarctation (n = 93)46 (49)41 (44)6 (6)
      Among patients with a prior intervention for RVH (n = 51)17 (33)29 (57)5 (10)
      Among patients without a prior intervention for RVH (n = 118)57 (48)49 (42)12 (10)
      Among patients with NF1 (n = 31)9 (29)16 (52)6 (19)
      Among patients without NF1 (n = 138)65 (47)62 (45)11 (8)
      Among patients with NF1 and concurrent aortic treatment (n = 19)3 (16)11 (58)5 (26)
      Among patients <3 years at operation (n = 21)7 (33)12 (57)2 (10)
      Among patients ≥3 years of age at operation (n = 148)67 (45)66 (45)15 (10)
      NF1, Neurofibromatosis type 1; RVH, renin-mediated renovascular hypertension.
      Values are reported as number (%).
      a Includes primary index and secondary operations.

      Discussion

      Renin-mediated hypertension secondary to renal artery stenoses and abdominal aortic coarctation is an uncommon cause of high blood pressure in childhood. The authors' institutional history of treating occlusive lesions of the renal arteries and abdominal aorta in pediatric patients has extended for more than four decades. Postoperative blood pressure control has appeared best in treating patients with isolated renal artery narrowings, as evident in the first University of Michigan report in 1973 citing 95% cure and 5% failure rates among 22 children undergoing renal artery reconstructive surgery.
      • Fry W.J.
      • Ernst C.B.
      • Stanley J.C.
      • Brink B.
      Renovascular hypertension in the pediatric patient.
      By 1981, that surgical experience increased to 34 children having isolated renal artery stenoses and 6 (15%) with coexistent renal artery stenoses and abdominal coarctations.
      • Stanley J.C.
      • Fry W.J.
      Pediatric renal artery occlusive disease and renovascular hypertension. Etiology, diagnosis, and operative treatment.
      In those having isolated renal artery disease, the hypertension cure, improved, and failure rates were 88%, 9%, and 3%, respectively, in contrast to 67%, 33%, and 0%, respectively, among those undergoing concurrent aortic reconstructions.
      An expanded University of Michigan report in 1995 validated this discrepancy in hypertension benefit, noting cure, improved, and failure rates of 88%, 10%, and 2% among children treated for isolated renal artery disease and 60%, 40%, and 0% for those undergoing coexisting aortic interventions.
      • Stanley J.C.
      • Zelenock G.B.
      • Messina L.M.
      • Wakefield T.W.
      Pediatric renovascular hypertension: a thirty-year experience of operative treatment.
      The authors subsequently observed a decline in cure rate over time from 81% (1963-1972) to 58% (1994-2006).
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      In addition, the authors' reported a cure rate of only 25% for remedial operations performed in 24 children after failed endovascular therapy.
      • Eliason J.L.
      • Coleman D.M.
      • Criado E.
      • Kershaw D.B.
      • Blatt N.B.
      • Williams D.M.
      • et al.
      Remedial operations for failed endovascular therapy of 32 renal artery stenoses in 24 children.
      The University of Michigan experience has become increasingly complicated in that failures of previous open surgical and endovascular procedures performed elsewhere now affect approximately a third of children with RVH referred to the authors for treatment. In addition, the complexity of the disease being treated has increased, with concurrent abdominal aortic coarctations affecting 45% of the current series' children. In comparison to our earlier experience, the overall hypertension cure rate has decreased to 44%. Although this is below cures generally reported in the past by high-volume centers, it is in line with the 46% cure rate reported by a contemporary report of 37 children from Great Ormond Street Hospital for Children (London, United Kingdom).
      • Stadermann M.B.
      • Montini G.
      • Hamilton G.
      • Roebuck D.J.
      • McLaren C.A.
      • Dillon M.J.
      • et al.
      Results of surgical treatment for renovascular hypertension in children: 30 year single centre experience.
      It is hypothesized that this reflects the increased rates of the performance of secondary revascularizations undertaken as salvage procedures after earlier failed interventions.
      • Stadermann M.B.
      • Montini G.
      • Hamilton G.
      • Roebuck D.J.
      • McLaren C.A.
      • Dillon M.J.
      • et al.
      Results of surgical treatment for renovascular hypertension in children: 30 year single centre experience.
      • Martinez A.
      • Novick A.C.
      • Cunningham R.
      • Goormastic M.
      Improved results of vascular reconstruction in pediatric and young adult patients with renovascular hypertension.
      • O'Neill Jr., J.A.
      Long-term outcome with surgical treatment of renovascular hypertension.
      Whereas NF1 and failure of an initial intervention were identified by univariate analysis to be associated with lesser blood pressure benefits, prior failures were the single independent predictor that children undergoing secondary operations were less likely to be cured of their hypertension. Such may represent an effect of the prior intervention or existence of more resistant underlying disease. Further study is needed to clarify this observation.
      Abdominal aortic coarctation is a rare disease, and the resulting blood pressure elevations can be severe and often difficult to control medically. The authors have previously reported salutary outcomes exceeding 90% among patients with the aortic narrowings having a mean age of 11.9 years.
      • Stanley J.C.
      • Criado E.
      • Eliason J.L.
      • Upchurch Jr., G.R.
      • Berguer R.
      • Rectenwald J.E.
      Abdominal aortic coarctation: surgical treatment of 53 patients with a thoracoabdominal bypass, patch aortoplasty, or interposition aortoaortic graft.
      Among the earlier report's patients exhibiting hypertension, cure and improved rates were 56% and 38%, respectively. The present data expand on this phenotype, supporting hypertension benefit in 86% of treated patients with abdominal aortic coarctation (37% cure, 49% improvement). Nevertheless, significant knowledge gaps remain regarding the pathogenesis of this disease and its clinical management. The question exists as to whether the aortic procedure itself may cause abnormal flow patterns to the kidneys that initiate persistent excessive renin release.
      • Courtel J.V.
      • Soto B.
      • Niaudet P.
      • Gagnadoux M.F.
      • Carteret M.
      • Quignodon J.F.
      • et al.
      Percutaneous transluminal angioplasty of renal artery stenosis in children.
      Such events may account for the poorer outcomes after aortic procedures observed in clinical practice.
      The Hospital for Sick Children (Toronto, Canada) recently reported a 30-year experience with renal and aortic stenosis that included 93 pediatric patients, of whom 51 had abdominal aortic coarctations.
      • Rumman R.K.
      • Matsuda-Abedini M.
      • Langlois V.
      • Radhakrishnan S.
      • Lorenzo A.J.
      • Amaral J.
      • et al.
      Management and outcomes of childhood renal artery stenosis and middle aortic syndrome.
      One-third of the children underwent open surgical interventions, but 53 underwent endovascular management of their renal artery lesions as a first intervention. The probability of undergoing an endovascular first intervention varied among the children. Those with abdominal aortic coarctations had a 60% lower risk of being treated by endovascular means compared with those with isolated renal artery stenoses. Importantly, 65% of that series' children remained hypertensive with a median follow-up of 2 years.
      Secondary intervention to preserve primary patency of a renal artery revascularization, often at anastomotic suture lines, or nephrectomy for a failed reconstruction was undertaken in 13% of the current series. This supports the importance of regular surveillance postoperatively, especially during periods of rapid childhood growth. Moreover, as evident in this study, secondary interventions are invariably more complex. Although most earlier reports have not emphasized progression of renal artery or aortic branch disease, this report did identify 13 children (18%) who required an operation for evolving disease that became clinically relevant after the primary index operation, as exemplified by patients whose previously normal contralateral main renal artery or segmental renal artery became stenotic over time and with growth, resulting in clinically significant recurrent renin-mediated hypertension.
      Endovascular interventions are increasingly reported as a means of treating pediatric renovascular disease. Although technically feasible, the blood pressure benefits remain inferior to open revascularizations, with benefit in many series ranging from 54% to 69%.
      • Srinivasan A.
      • Krishnamurthy G.
      • Fontalvo-Herazo L.
      • Nijs E.
      • Keller M.S.
      • Meyers K.
      • et al.
      Angioplasty for renal artery stenosis in pediatric patients: an 11-year retrospective experience.
      ,
      • Shroff R.
      • Roebuck D.J.
      • Gordon I.
      • Davies R.
      • Stephens S.
      • Marks S.
      • et al.
      Angioplasty for renovascular hypertension in children: 20-year experience.
      ,
      • Courtel J.V.
      • Soto B.
      • Niaudet P.
      • Gagnadoux M.F.
      • Carteret M.
      • Quignodon J.F.
      • et al.
      Percutaneous transluminal angioplasty of renal artery stenosis in children.
      Endovascular restenosis has been well described after pediatric renal artery angioplasty, ranging from 7% to 44% of interventions, being more frequent after treatment of renal stenoses in children having defined syndromes like NF1. In addition, the benefits from secondary open operations in these children are limited.
      • Rumman R.K.
      • Matsuda-Abedini M.
      • Langlois V.
      • Radhakrishnan S.
      • Lorenzo A.J.
      • Amaral J.
      • et al.
      Management and outcomes of childhood renal artery stenosis and middle aortic syndrome.
      ,
      • Sharma S.
      • Thatai D.
      • Saxena A.
      • Kothari S.S.
      • Guleria S.
      • Rajani M.
      Renovascular hypertension resulting from nonspecific aortoarteritis in children: midterm results of percutaneous transluminal renal angioplasty and predictors of restenosis.
      ,
      • Tyagi S.
      • Kaul U.A.
      • Satsangi D.K.
      • Arora R.
      Percutaneous transluminal angioplasty for renovascular hypertension in children: initial and long-term results.
      Our current practice considers renal artery angioplasty for mid and distal renal artery and segmental stenoses that appear multifocal, weblike, or beaded by arteriography or with intravascular ultrasound, whereas we continue to favor primary reimplantation for ostial or proximal main renal artery stenosis and open surgical revascularization of unifocal stenoses of the mid, distal, or segmental renal arteries that appear hypoplastic by arteriography or intravascular ultrasound. Also, regardless of age, angioplasty is favored for recurrent stenosis at suture lines from neointimal hyperplasia. It is the authors' opinion that renal and aortic stenting should be avoided in pediatric patients and employed only for salvage cases. Treatment decisions are made collaboratively by our multidisciplinary team, which includes representation from vascular surgery, pediatric nephrology, and interventional radiology. The surgical approach to renal revascularization at the University of Michigan has varied little in recent decades.
      • Stanley J.C.
      • Criado E.
      • Upchurch Jr., G.R.
      • Brophy P.D.
      • Cho K.J.
      • Rectenwald J.E.
      • et al.
      Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.
      In situ reconstruction is favored to preserve important collaterals and to limit intraoperative warm ischemia, even in cases of distal or segmental disease and multiple renal arteries. Ex vivo reconstruction was employed for a single patient in this series with a complex, distal left renal artery aneurysm with multiple existing segmental arteries. Reimplantation onto the aorta of the normal renal artery, beyond its stenosis, when possible, remains the preferred surgical technique for renal revascularization. Care is taken to carefully spatulate the renal artery to create a generous orifice for reimplantation. The anastomoses are completed with interrupted fine monofilament sutures to permit future growth in infants and the very young. In children requiring an aortorenal bypass, vein grafts are avoided because of the risk of late aneurysmal changes. The hypogastric artery is favored as a conduit in these instances. Concerns have previously been raised about the procurement of the hypogastric artery in children regarding the risk of pelvic ischemia. In the University of Michigan experience, there have been no cases of buttock claudication or genitourinary dysfunction, and five children (four girls, one boy) having excision of their internal iliac artery have gone on to successfully have children.
      Concurrent aortic revascularization was common in this series' children. Patch aortoplasty, when feasible, remains the authors' preferred technique for aortic revascularization. However, aortoaortic bypass, often originating from the supraceliac abdominal aorta or descending thoracic aorta, is favored in children having a narrow abdominal aortic coarctation. In these cases, arterial patch-aortic anastomotic suture lines would nearly overlap. The type of aortic revascularization (patch or bypass) did not significantly affect blood pressure benefits postoperatively. The preferred conduit for both a patch aortoplasty and an aortic bypass is ePTFE, given the recognized later aneurysmal deterioration of Dacron. Whenever possible, patches and grafts are sized sufficiently large enough so as not to become constrictive as the child grows into adulthood. The authors recommend regular postoperative surveillance to include the following: regular monitoring of blood pressure and renal function by the primary nephrologist; annual renal duplex ultrasound examination to monitor renal size/mass and velocities; annual ankle-brachial index to assess lower extremity perfusion in cases of aortic reconstruction; cross-sectional imaging every other year to assess aortic reconstructions, during years of long growth; and ambulatory blood pressure monitoring and echocardiography for concerns related to poorly controlled hypertension or symptoms. Any concern for recurrent stenosis and recurrent hypertension should prompt further investigation with catheter-based arteriography.
      Limitations to this single-center retrospective study are intrinsic to the study design and compounded by the diverse geographic location of the patients' residence and common international/out-of-state referral patterns. Specifically, some patients were lost to long-term follow-up, introducing the potential for type II error in that some patients may have required secondary procedures elsewhere; 105 patients (62%) have not had follow-up at our center or correspondence within the preceding 24 months. Importantly, whereas the authors recommend judicious postoperative surveillance, this is often performed locally for those international and out-of-state patients. As such, records are not consistently or widely available for all patients despite contemporary efforts and requests for such, limiting available follow-up data. In addition, cure as used in this study applies to a hypertension cure during available follow-up, as defined before. This is a limited definition and does not consider longitudinal follow-up into late adulthood. Clinically speaking, use of the word cure should be severely tempered for cases of childhood arterial dysplasia. Cohort development and longer prospective longitudinal follow-up are urgently required to enhance our understanding of the natural history of pediatric RVH with medical management and revascularization that consider patient phenotype and optimize indications for and timing of invasive treatment.

      Conclusions

      The contemporary surgical treatment of pediatric RVH due to renal artery occlusive disease and aortic coarctation requires an individualized approach that considers the patient's age, the severity of the hypertension, the underlying disease, and the vascular anatomy, including that of extrarenal disease. Open revascularization of both renal artery stenoses and abdominal aortic coarctations at a high-volume referral center provides sustainable benefits in nearly 90% of children. Nevertheless, interventions in the very young (<3 years) and the presence of concurrent aortic disease increase the likelihood of a later reoperation. Those undergoing secondary procedures are less likely to be cured of hypertension. Postoperative surveillance in children treated for RVH is imperative, given the risk of restenoses and disease progression. Established criteria for the diagnosis and management of pediatric RVH must consider specific patient phenotypes to define the most appropriate interventions and to identify best practices, especially in balancing the risks of open operative and endovascular interventions. Further prospective, multicenter investigation of this rare but debilitating condition is urgently required to improve the outcomes and quality of life for affected children.

      Author contributions

      Conception and design: DC, JE, DK, ZM, MSK, DW, JS
      Analysis and interpretation: DC, JE, MK, SG, JS
      Data collection: DC, RB, TJ
      Writing the article: DC
      Critical revision of the article: DC, JE, RB, TJ, MK, DK, ZM, SG, MSK, DW, JS
      Final approval of the article: DC, JE, RB, TJ, MK, DK, ZM, SG, MSK, DW, JS
      Statistical analysis: DC, MK
      Obtained funding: JE, SG, JS
      Overall responsibility: DC

      Appendix (online only).

      Supplementary Table I (online only)Logistic regression model to predict the odds of reoperation
      Independent variablesUnadjusted OR (95% CI)P valueAdjusted OR (95% CI)P value
      Age at operation0.88 (0.81-0.95).0020.86 (0.77-0.95).003
      No. of initial medications1.09 (0.87-1.38).4490.90 (0.68-1.19).450
      Aortic reconstruction
       NoneReferenceReference
       Patch0.46 (0.15-1.43).1780.11 (0.02-0.54).007
       Bypass0.74 (0.27-2.00).5500.27 (0.06-1.19).084
      NF1
       NoReferenceReference
       Yes1.76 (0.73-4.27).2101.26 (0.43-3.68).671
      Abdominal aortic coarctation
       NoReferenceReference
       Yes1.60 (0.76-3.39).2166.01 (1.70-21.24).005
      Had a prior intervention
       NoReferenceReference
       Yes1.27 (0.58-2.80).5531.61 (0.60-4.31).309
      CI, Confidence interval; NF1, neurofibromatosis type 1; OR, odds ratio.
      Supplementary Table II (online only)Ordinal regression model to predict hypertension benefit
      Independent variablesUnadjusted OR (95% CI)P valueAdjusted OR (95% CI)P value
      Age at operation1.05 (1.00-1.11).0681.05 (0.98-1.12).176
      No. of initial medications0.85 (0.71-1.02).0890.87 (0.71-1.06).161
      Aortic reconstruction
       NoneReferenceReference
       Patch0.65 (0.30-1.38).2610.86 (0.28-2.62).795
       Bypass0.60 (0.28-1.30).1940.53 (0.18-1.62).271
      NF1
       NoReferenceReference
       Yes0.42 (0.20-0.91).0280.48 (0.21-1.08).075
      Abdominal aortic coarctation
       NoReferenceReference
       Yes0.55 (0.31-1.00).0500.75 (0.28-1.97).58
      Had a prior intervention
       NoReferenceReference
       Yes0.62 (0.33-1.16).1430.49 (0.25-0.98).042
      CI, Confidence interval; NF1, neurofibromatosis type 1; OR, odds ratio.

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