PEDIATRICS Vol. 118 No. 1 July 2006, pp. 268-275 (doi:10.1542/peds.2005-2642)
Angioplasty for Renovascular Hypertension in Children: 20-Year Experience
a Departments of Nephrourology
b Radiology, Great Ormond Street Hospital for Children, London, United Kingdom
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ABSTRACT |
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OBJECTIVE. Our aim was to evaluate the clinical outcomes, safety, and efficacy of percutaneous transluminal angioplasty for renovascular hypertension in children.
METHODS. A retrospective review of data for all children with renovascular hypertension who underwent percutaneous transluminal angioplasty at a single center between 1984 and 2003 was performed. Patients with renal transplants and inflammatory multisystem diseases were excluded.
RESULTS. Thirty-three children, 1.9 to 17.9 years of age (median: 10.3 years), underwent renal angioplasty and/or stenting. Underlying syndromes were present in 10. On angiograms, 16 had bilateral renal artery stenosis, 15 intrarenal disease, 8 aortic stenosis, and 7 cerebrovascular disease. Forty-eight percutaneous transluminal angioplasty procedures were performed, including 15 stenting procedures. There was a high rate of restenosis after stenting (7 of 19 cases, compared with 2 of 27 cases after balloon dilation). Outcomes were cured (ie, blood pressure normal without treatment) for 9 patients, improved blood pressure with same or reduced treatment for 7, blood pressure maintained in >95th percentile because of cerebrovascular disease for 2, no change in blood pressure despite technical success for 10, and technical failure for 5. Blood pressure control improved in 11 of 13 children who had main renal artery disease alone and in 6 of 20 with associated intrarenal disease or stenoses in other vascular beds. There was 1 procedure-related death and 5 minor complications.
CONCLUSIONS. Angioplasty produced clinically worthwhile improvement for 
50% of patients. High incidence rates of extrarenal involvement and intrarenal disease and a high restenosis rate after stenting accounted for poor blood pressure control in the rest.
Key Words: renovascular hypertension • child • renal artery stenosis • percutaneous transluminal angioplasty • stent • restenosis
Abbreviations: RVH—renovascular hypertension • RAS—renal artery stenosis • PTA—percutaneous transluminal angioplasty • NF1—neurofibromatosis type 1 • BP—blood pressure • FMD—fibromuscular dysplasia • DMSA—dimercaptosuccinic acid
Renovascular disease is an important cause of remediable hypertension and accounts for 10% of all cases of secondary hypertension in children.1–3 Renovascular hypertension (RVH) can be defined as hypertension resulting from a lesion (or lesions) that impairs blood flow to a part, or all, of one or both kidneys.4 Unlike adults, among whom the disease is almost invariably atherosclerotic in nature,5 children with RVH are more likely to have fibromuscular dysplasia (FMD),6 with bilateral and segmental disease and involvement of the small intrarenal arteries4,6–8 and other vascular beds.8,9 Adequate control of blood pressure (BP) is often impossible despite the use of several antihypertensive agents. Adverse effects of the drugs and problems with compliance are common. Moreover, if BP is normalized with medications, then underperfusion of the kidney, with its stenosed vasculature, may result in renal impairment. When medical treatment fails to control BP optimally, various endovascular procedures or surgical revascularization must be considered. We present our 20-year data for all children who underwent percutaneous transluminal angioplasty (PTA) for treatment of RVH; we describe the mode of presentation, details of the endovascular procedure (performed by interventional radiologists in our center), and early- and long-term outcomes and complications.
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METHODS |
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Patient Group and Study Design
This was a single-center, retrospective, longitudinal, follow-up study of all children who underwent PTA for treatment of RVH at Great Ormond Street Hospital between January 1984 and December 2003. The study was approved by the local ethics committee.
Patients with RVH were identified from medical records in the departments of pediatric nephrology and radiology. Patients who had main or large segmental renal artery stenosis (RAS) and underwent PTA were included in this study. Patients with inflammatory multisystem diseases (such as polyarteritis nodosa) or stenosis of transplant arteries were excluded. The patients' demographic details, underlying syndromes, mode of presentation, BP, and antihypertensive drugs were recorded through retrospective review of medical records.
To identify lesions potentially remediable with PTA, all patients underwent precaptopril and postcaptopril scintigraphy with dimercaptosuccinic acid (DMSA) labeled with technetium-99m and selective renal vein renin sampling with segmental sampling. Details of these procedures and their diagnostic value in childhood renovascular disease were described in previous reports from this center.4,10–12 All children underwent diagnostic angiography before any interventional or surgical procedure; this remains the standard method for diagnosis of any renal arterial pathologic condition.13 It is not always possible to determine which children have cerebral arterial involvement on the basis of the nature or extent of their renal vascular disease.4,9 Therefore, cerebral perfusion was assessed for all children with single-photon emission tomography with hexamethylpropyleneamineoxime labeled with technetium-99m; in our experience, this method helpfully identified significant decreases in perfusion associated with major arterial stenosis. Cerebral angiography was performed in selected cases, when clinical signs (such as a cranial bruit) or perfusion study data suggested functionally important arterial pathologic conditions.
Decisions regarding treatment were based on several factors, including patient age and size, extent of disease, natural history of the lesions, technical difficulty, and ease of medical treatment. Each patient was evaluated on an individual basis by a multidisciplinary team (including a nephrologist, an interventional radiologist, and a vascular surgeon), for assessment of the potential benefits of the various treatment modalities. Our indications for angioplasty have been evolving and are several, namely, to decrease the burden of drug therapy and to avoid or in some cases to delay the need for complex revascularization surgery until the child is old enough to undergo definitive surgery. In recent years, we have also attempted angioplasty in patients with extensive arterial disease, sometimes as a last-ditch attempt to offer some relief from the hypertension. Stenting of the renal arteries is a recent option, which we have used since 2002. Our indications for renal artery stenting are (1) immediate recoil after angioplasty, (2) flow-limiting arterial dissection caused by angioplasty, and (3) very early recurrence of RAS after technically and clinically successful angioplasty. Endovascular procedures were not attempted for children with disease of peripheral intrarenal arteries alone.
Angioplasty Technique
All procedures were performed with general anesthesia. The technical aspects of angiography and angioplasty evolved considerably during the period covered by this study.13 Procedures were performed through femoral arterial access when possible. After diagnostic angiography, the RAS was crossed with a guidewire and angioplasty catheter. The balloon diameter used was 2 to 6 mm and corresponded to the estimated normal diameter of the stenotic segment and not that of the poststenotic segment, which might be abnormally large. Heparin was administered intraarterially (typically at 50–100 U/kg) before the balloon was inflated. Coronary angioplasty catheters (diameter: 2–4 mm) were used in main renal arteries of small children and in segmental arteries. Premounted balloon-expandable stents (including coronary stents) were used when indicated.
A technically successful procedure was defined by a sustained increase in blood vessel diameter, as confirmed with immediate repeat angiography. DMSA scintigraphy was repeated for all patients, to look for changes in renal function after angioplasty. Restenosis was suspected when the patient had a rebound increase in BP after a period of improvement after PTA and when narrowing of the previously dilated vessel was demonstrated with angiography.
Follow-up Monitoring and Assessment of Outcomes
All patients were monitored to December 2003. Teenagers who were transferred to adult services were monitored through written requests to their new physicians. Assessment of outcomes was based on the criteria suggested by Ellis et al,14 as follows: (1) "cured," with normal BP (<95th percentile for age, gender, and height) with no antihypertensive treatment; (2) improved BP with same or reduced treatment; (3) no change in BP despite angiographic success; or (4) technical failure (ie, unable to pass balloon catheter or unable to dilate vessel with balloon).
To these criteria, we added in a fifth category, namely, BP maintained in >95th percentile because of cerebrovascular disease. This allowed us to describe the group of patients with severe cerebrovascular disease and RVH for whom a reduction of BP to recommended normal levels resulted in inadequate cerebral perfusion, manifested clinically as poor concentrating ability, drowsiness, and seizures.
Statistical Analyses
Results have been described as median and range. The results of balloon dilation alone versus balloon dilation and stenting were compared with the Mann-Whitney U test.
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RESULTS |
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Study Group
One hundred nine children with RVH were treated at Great Ormond Street Hospital between January 1984 and December 2003. Of these, approximately one third of the children received medical treatment alone, one third required surgical revascularization, and one third (n = 33) underwent PTA for treatment of stenosis of the main or large segmental native renal artery or arteries or a surgical graft and were included in this study.
Demographic Features
The median age at referral was 8.4 years (range: 0.5–17 years). There were 22 boys (66%). Patients were referred from general pediatric units (n = 17; 51%), from pediatric nephrology centers both within the United Kingdom (n = 6; 18%) and in other countries (n = 7; 21%), and through the cardiology department at Great Ormond Street Hospital (n = 3; 9%).
Presentation
The most common presenting feature was an incidental finding of hypertension, but older children often had cardiac or neurologic signs (Table 1). Ten patients (30%) had underlying syndromes, neurofibromatosis type 1 (NF1) in 8 patients (28%) and William's syndrome and velocardiofacial syndrome in 1 patient each. No child had features of Takayasu's arteritis.
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The median systolic BP at referral was 159 mm Hg (range: 130–240 mm Hg). The median BP above the 95th percentile for age, gender, and height1,15 was 52 mm Hg (range: 27–126 mm Hg). The children were taking 1 to 6 antihypertensive medications (median: 4 medications) at referral. Patients were treated with antihypertensive agents according to the existing protocol used at Great Ormond Street Hospital. There was electrocardiographic and/or echocardiographic evidence of left ventricular hypertrophy for 22 patients (66%), with 3 patients (9%) in congestive cardiac failure. Hypertensive retinopathy was present for 10 children (33%) at presentation. None of the patients had known renal disease at presentation. The median estimated glomerular filtration rate (determined with the Schwartz formula) was 101 mL/minute per 1.73 m2 (range: 43–134 mL/minute per 1.73 m2); only 2 children had glomerular filtration rates of <80 mL/minute per 1.73 m2. Thirty-seven percent of the children had proteinuria.
Diagnostic Angiography
Sixteen patients (48%) had bilateral RAS and 15 (45%) had intrarenal disease. Ten patients (30%) had both bilateral RAS and intrarenal disease. Midaortic involvement was present in 8 patients (24%); this was associated with both bilateral RAS and intrarenal disease in 5 patients and with cerebral vascular involvement in 4 patients. All of the children with mesenteric vessel involvement (n = 10; 30%) also had midaortic stenosis. Seven children had cerebrovascular involvement and were the most severely affected, with associated bilateral RAS and intrarenal disease in 6 (86%) and midaortic involvement in 4 (57%). Isolated narrowing of a segmental renal vessel was found for 3 children.
The types of main RAS (49 arteries) observed with angiography were long-segment stenosis (n = 26; 60%), ostial stenosis (n = 11), ostial and long-segment stenosis (n = 6), aneurysmal dilation (n = 3), and webs (n = 3). Angiographic appearances were similar for children with and without NF1 and were broadly compatible with the reported findings for FMD.6 Classification of each patient into one of the various subtypes of FMD6 was not possible, however, because of overlapping angiographic findings. Histologic diagnosis was possible for only 3 of the 8 children who also received surgical treatment; all had FMD.
Angioplasty
Forty-eight PTA procedures were performed for the 33 patients during the study period; 21 patients required 1 procedure only, 9 required 2 procedures. and 3 required 3 procedures each (Table 2). Five patients had bilateral PTA procedures performed, and 3 patients underwent PTA for treatment of stenosis of large segmental arteries. The median age at the time of the first PTA procedure was 10.3 years (range: 1.9–17.9 years), with the median interval between referral and PTA being 0.6 years (range: 0–11 years).
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The techniques used for PTA included balloon dilation alone, balloon dilation with stenting, use of a cutting balloon, balloon dilation for in-stent stenosis, and dilation of a stenosed synthetic graft (Figs 1 and 2). Of the 33 patients undergoing their first PTA procedure, 21 (66%) required balloon dilation alone, 10 underwent balloon dilation and stenting, and 2 who had previously undergone surgical revascularization underwent dilation of their synthetic grafts. Twelve patients required a second procedure; 1 underwent balloon dilation alone, 6 underwent balloon dilation with stenting (including use of a cutting balloon for 1), and 7 who developed restenosis after their primary procedure underwent balloon dilation. Three patients underwent a third procedure; 1 required stenting for recurrence of stenosis. The early outcomes (at 3 months after the procedure) and the indications for repeat procedures are described in Table 2.
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Restenosis
With exclusion of the 2 procedures involving dilation of synthetic grafts, restenosis occurred in only 2 (7.4%) of 27 native renal arteries that were balloon dilated. However, 7 (36.8%) of 19 arteries that required stent insertion developed restenosis (P < .001).
Final Outcomes of PTA
At the final follow-up assessments, 18 (55%) of the 33 patients achieved an improvement in BP control (Table 3). Eleven (85%) of the 13 patients with main RAS alone, irrespective of unilateral or bilateral involvement, experienced improvement in BP control. Ten patients (30%) continued to have high BP despite adequate dilation, and PTA was technically unsuccessful for 5 (15%). In the group (n = 10) with persistently high BP despite angiographic success, 8 had stenoses in other vascular beds (intrarenal disease in 3, midaortic syndrome in 2, and intrarenal disease, midaortic narrowing, and cerebrovascular disease in 3) and 2 developed residual stenosis that could not be redilated. Among the 5 patients for whom angioplasty was unsuccessful (median age: 6.6 years; range: 2.5–15.5 years), the stenoses were too narrow for passage of a balloon catheter in 2 (both had ostial stenosis of the renal artery) and ballooning was unable to achieve adequate sustained dilation of the vessel in 3. Four of these 5 patients underwent angioplasty in the early 1980s, when pediatric angioplasty was in its infancy and appropriately sized vascular catheters and cutting balloons were not available.
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Renovascular Disease in NF1
Eight children (25%) in this series had NF1. Of these, 7 had bilateral RAS, 2 had bilateral RAS with intrarenal disease, 2 had intrarenal disease and midaortic syndrome, and 1 had intrarenal disease, midaortic syndrome, and cerebrovascular disease. Compared with the overall patient group, the children with NF1 had similar outcomes with angioplasty; BP improved for the 3 children with main RAS alone (unilateral or bilateral), whereas the rest, with more-widespread stenosis, were hypertensive despite angiographic success.
Complications
Complications of PTA occurred in 6 (18%) of the 33 patients, including a procedure-related death described below. Renal artery thrombosis occurred in 1 patient, presenting with hypertension and loin pain within 4 hours after PTA. Emergency revascularization surgery with a saphenous vein graft was performed, with reperfusion of the kidney and normalization of BP. In 1 patient, a stent detached prematurely from the delivery catheter, causing iliac artery dissection. Femoral arteriotomy was required to remove the defective stent, and the dissection flap was treated with angioplasty. Two patients developed new focal defects, detected with 99mTc-DMSA scintigraphy performed 2 to 5 months after PTA; their overall renal function was unaffected, however. One patient developed a small groin hematoma.
Deaths
There were 2 deaths during the study period; 1 was procedure-related. One patient, 5.5 years of age, developed fatal hemorrhage from a graft tear after repeat angioplasty for a synthetic graft to a solitary kidney. This patient had presented at the age of 2 years with a cerebrovascular accident. He had bilateral RAS, intrarenal disease, midaortic syndrome, and cerebrovascular disease. After 2 failed attempts at PTA for one kidney (the stenosis was too narrow to pass a balloon catheter) and a failed attempt at surgical revascularization of the kidney, the patient underwent unilateral nephrectomy and a synthetic graft was placed across the stenosed contralateral renal artery. Despite these attempts, the patient's systolic BP remained 180 mm Hg with 7 antihypertensive agents. Balloon dilation of the synthetic graft was performed on 2 occasions; in the second attempt at dilation, the patient developed fatal hemorrhage from the graft tear. The second death in this study involved a 16.8-year-old girl who developed fatal dysrhythmia secondary to myocardial fibrosis resulting from severe hypertension. The hypertension was unresponsive to medical therapy and the RAS was not amenable to angioplasty. The patient had severe bilateral RAS with intrarenal involvement and also had cerebrovascular disease, which might have been responsible for the hypertension and was not amenable to cerebral revascularization surgery. Despite treatment with 6 antihypertensive agents, the patient's systolic BP remained 150 mm Hg. After an episode of dehydration, the patient developed renal venous thrombosis and lost one kidney. Angioplasty was attempted on the contralateral side but did not improve BP control, probably as a consequence of severe aortic and intrarenal disease. In the postmortem examination, severe myocardial fibrosis resulting from longstanding uncontrolled hypertension was seen.
Surgery
Six patients required surgical revascularization, with 2 procedures in 1 patient. BP control improved for 4 of the 6 patients, with 2 patients discontinuing all antihypertensive treatment. The details of the surgical revascularization will be described in a separate report. Two patients required dilation of their Gore-Tex grafts after revascularization surgery (median time after surgery: 3.1 years).
Follow-up Monitoring
All patients were monitored to December 2003. Seventeen patients were still reviewed at Great Ormond Street Hospital, 8 had been transferred to local adult nephrology centers, 6 were treated in their referring centers outside the United Kingdom, and there were 2 deaths. The median follow-up time for the 25 patients in the United Kingdom was 11.9 years (range: 1.1–14.2 years). At the final follow-up assessments, after all PTA procedures and surgery, 21 (84%) of the 25 patients demonstrated improvement in their BP, with 11 discontinuing all antihypertensive medications. Three patients remained hypertensive with either the same or increased doses of antihypertensive treatment, and 1 patient had uncontrolled hypertension. Two patients had chronic renal insufficiency, but none required dialysis.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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RAS is the third most common pathologic condition2,3 (after renal scarring and glomerular disease) giving rise to significant sustained hypertension in children. It accounted for 8.5% of all referrals for hypertension at Great Ormond Street Hospital during a 10-year period.2 We describe the outcomes of PTA in 33 children with complex renovascular disease. Because this study spans a 20-year period, with improvements in technology and the availability of smaller catheters and cutting balloons for resistant stenoses, complex cases are now better managed and increasingly more challenging cases are being attempted. In our series, PTA was successful in just more than one half of the patients, with 54% achieving improved BP control and 27% of them having discontinued all antihypertensive treatment at the final follow-up assessment.
Although the association between renovascular disease and widespread arterial involvement has been reported,2,4,8,9,16 it seemed to be more extensive in our cohort than in other series,7,14,17–23 in which extensive investigations for widespread vascular stenoses were not performed. In our series, bilateral RAS was seen in 48% of patients and intrarenal disease in 45% of patients. In addition, there was a high incidence of involvement of other vascular beds, particularly the brain (n = 7; 21%) and aorta (n = 8; 24%), in this study. Reportedly, the carotid and vertebral arteries are involved in 25% to 30% of patients with FMD,5,9 and a non-Takayasu midaortic syndrome is well recognized in children.24 Seven of our patients had severe cerebrovascular involvement. We recommend routine cerebrovascular imaging for all children with RVH, because it is not possible to predict cerebrovascular disease on the basis of the nature or extent of the renal vascular involvement. However, some children manifest clinical signs of cerebral ischemia or have audible bruits over the orbits, temporal regions, or carotid arteries that suggest underlying pathologic conditions. Although single-photon emission tomography was used in our practice, newer magnetic resonance imaging techniques that image the cerebral vessels as well as brain parenchyma would allow better assessment of the cerebrovascular involvement. In cases in which cerebral revascularization is considered, conventional angiography may be necessary.
Given the often widespread nature of renovascular disease in children, treatments may include medical therapy, angioplasty, and/or revascularization surgery, with unilateral nephrectomy in some cases. Traditionally, RVH was treated with vascular surgery, with the first successful renal artery angioplasty in a child being reported in 1980.25 After early pioneering work26–29 in the field of pediatric renovascular disease, several small case series on selected patient groups, with varying success rates (25–94%),6,13,17–22 were reported (Table 4; only series with 
5 children are quoted, to avoid publication bias). However, the pathophysiologic features,6,29–32 distribution,9,33 and potential for progression of the vascular involvement can influence significantly the outcome of angioplasty, which makes comparisons between groups difficult. Takayasu's arteritis30,34–36 is the most common cause of renovascular disease in Asia and Africa, whereas most children in western countries have FMD4,6,31 or the vascular lesions of NF1.20,32,37 As seen in this series and in Table 4, intrarenal disease or the presence of aortic or cerebrovascular disease influences the final BP outcome strongly. In our series, unlike in previous reports,20,37 the BP outcomes for the subgroup with NF1 were dependent on the presence and extent of extrarenal disease and did not differ from those for the other patients. Many of the case series involved selected groups of patients with single-vessel disease,7,17–19,22 who are not representative of the spectrum of renovascular disease seen in our hospital. Similarly, for adults with FMD, angioplasty produced improvement in BP control in 70% to 98% of patients,6 which suggests that the complex multivessel involvement in our patients likely contributed to their poor outcomes. BP control improved in 11 (85%) of 13 patients in our group with main renal artery disease alone, whereas only 6 (30%) of 20 patients with associated intrarenal disease or stenoses in other vascular beds benefited.
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We report a restenosis rate of 37% after stenting; this has not been mentioned in other pediatric series but is higher than rates reported in similar adult series38 and is not significantly different from the restenosis rate for adults with coronary artery stenosis who undergo stenting.39 Similar rates of restenosis in adults' coronary arteries and children's renal arteries may reflect the fact that these vessels are the same size; a fixed degree of neointimal hyperplasia (in millimeters) causes much greater reduction in cross-sectional area in small arteries. Vascular smooth muscle cells migrate from the media of the vessel wall into the lumen of the stent (neointimal proliferation), resulting in a clinically significant reduction in the luminal diameter of the stented vessel in
30% of cases.40 The smaller diameter of the vessel and the possible effect of growth factors on the child's vasculature4 may account for the higher restenosis rate than reported in adult series. Novel techniques involving drug-eluting stents were developed for adults with coronary artery stenosis,38,41 and early studies showed that sirolimus- or paclitaxel-eluting stents were superior to conventional stents. However, delayed or incomplete healing, with persistence of fibrin42 and incomplete coverage of the stent struts with endothelial cells, can give rise to delayed stent thrombosis, aneurysm formation, or extensive inflammatory reactions.42 More data on the long-term benefits and histologic changes in blood vessels of patients with drug-eluting stents are needed before we know how safe these stents are in children. Cutting balloons have recently become available to treat resistant arterial stenoses, and have been used successfully in 1 of the patients in this series. We expect these developments to increase the technical success rate of angioplasty to close to 100%. |
CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Angioplasty is a relatively safe and often effective treatment for RVH in children, producing clinically worthwhile improvement for more than one half of the patients. The high incidence of extrarenal involvement and intrarenal disease and the high rate of restenosis after stenting contributed to poor BP control in the rest of the patients.
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FOOTNOTES |
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Accepted Feb 6, 2006.
Address correspondence to Kjell Tullus, FRCPCH, Department of Nephrourology, Great Ormond Street Hospital, Renal Office, Frontage Building, Great Ormond Street, London WC1N 3JH, United Kingdom. E-mail: tulluk{at}gosh.nhs.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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