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CUBAN MEDICAL LITERATURE Hypertension in Children: Diagnosis and Treatment ABSTRACT INTRODUCTION Hypertension is not common in children.[1] Although it is generally agreed that early essential hypertension poses little immediate risk to most children, evidence from preliminary studies of children and adolescents has shown hypertensive heart disease and hemodynamic changes consistent with an adverse effect of mild hypertension before the third decade of life.[2-8] Secondary hypertension is more common in children than in adults and can lead to organ damage and increased mortality.[8] The cause is multifaceted, but renovascular hypertension (RVH) is an important cause of secondary hypertension in children accounting for 5% to 25% of cases.[5,7,8]. The exact prevalence of RVH in children is unknown. The most common cause is fibromuscular hyperplasia.[5-7,9-11] Other identified associated causes are coarctation of the aorta, different types of arteritis, neurofibromatosis and idiopathic hypercalcemia (Williams-Bueren syndrome).[3,6] We present a retrospective study in a population of hypertensive children with clinical suspicious signs of renovascular hypertension. The aim of the study was to evaluate a number of pediatric patients with hypertension during a 15-year period (1986-2000), and in so doing, make an early diagnosis of RVH and subsequently examine three separate therapies. We describe clinical, laboratory and radiological findings, management and patient outcome. MATERIALS AND METHODS Patients All hypertensive children age 2-18 referred to the hypertension clinic of the national Institute of Nephrology, were eligible for inclusion. All had at least one possible clinical sign of RVH (severe hypertension exceeding the 99th percentile for age and sex; resistance to antihypertensive medications; responses to ACE inhibitors; systo-diastolic peri-umbilical noise; or hypertensive encephalopathy), at the time of enrollment into a screening program for diagnosis and treatment of RVH from 1986 to 2001.[11] Hypertension was defined as systolic and /or diastolic blood pressure persistently above the 95th percentile for age, sex and height[1] for patients up to the age of 16; for those between the ages of 17 and 18, it was defined according to the WHO (>140/90 mmHg) regardless of gender. Screening Test A complete clinical examination, hematology, biochemical screening test, urinalysis, imaging studies, and peripheral and separate renal venous plasma renin activity (PRA) was obtained.[11,12] In addition, captopril-stimulated plasma renin tests were obtained in all cases (patients did not receive any antihypertensive medication for at least two weeks and were not salt depleted). The test was performed in the morning in fasting sitting position. After a 30-minute rest period in the supine position, a single dose of captopril 0.63+-0.05 mg/kg body weights was given. Blood sampling was collected before and 60 minutes after dosage for determination of plasma renin concentration (normal range 1 to 2.70 ng/ml/hr). Blood pressure was measured 10, 20 and 30 minutes before captopril administration to get baseline BP and every 15 minutes during an hour. PRA was measured by radioimmunoassay using a commercially available kit. According to the criteria of Muller et al. and Alfonzo et al.,[11] the captopril test was positive if the post-captopril PRA (ng/ml/hr) was greater than 12, with an increase of e” 10, and a relative increase of e” 15% (400% if initial PRA was <300). Measurement of renal vein renin levels was used to confirm the hemodynamic significance of confined renal artery stenosis. Ratio of <1.5:1 was considered significant and predicted a positive response to revascularization or nephrectomy for atrophic non-functioning kidney. 99mTc-diethylenetriaminepentaacetate (Tc-99mDTPA) or 99mTc-mercaptoacethylplicerine-MAG3 (Tc-99MAG-3) scintigraphy basal and post-captopril study were performed during the screening period in basal condition and one hour after oral administration of Captopril.[3,13] Images were obtained by means of a gamma camera (GE 400 AT) equipped with general purpose collimator after an intravenous injection of radionuclide. Each scintigraphic study was interpreted visually and according to renogram curve patterns. Semi-quantitative parameters (Tmax mean transit time, relative renal function (%) and renal output efficiency), were also calculated.[2,11,13,14] A scintigraphic study is considered pathological if the curve shows a delay peak (beyond six minutes Tmax) or there is an asymmetric renal function (>60% or <40%). Subtraction aorto-renal arteriography was performed in all cases (RVH significative stenosis >60% of lumen reduction), and selective renal arteriography pre and post PTA. The etiology of fibromuscular disease or arteritis was classified on the basis of the angiographic appearance as defined by McCormack LJ et al[15] in the absence of diabetes, neurofibromatosis, Takayasu arteritis atheromatosis of the aorta and its mayor branches, and young age of the patients. No material was available for histological analysis, except the atrophic kidneys after nephrectomy. Patient Follow-Up and Endpoints for Treatment Patients were seen at 1, 3, 5 and 10-year intervals in an outpatient setting after discharge from the hospital or initiation of drug therapy. During the remaining time, their pediatric or primary care physician followed the patient clinically and monitored medication dosage. The endpoints for treatment in all cases were: 1) blood pressure (BP) control, 2) serum creatinine as measurement of renal function, 3) the date of inclusion in a dialysis program or rise in creatinine to 4.5 mg/dl and 4) patient survival. Therapy Utilizing this array of procedures, we defined anatomical and functional status of renal vasculature in order to be guided towards the most appropriate therapeutic option. Once diagnosis was established, three therapeutic modalities were chosen: 1) medical therapy with antihypertension drugs in non-RVH patients, patients awaiting angioplasty or revascularization, and those who have failed to respond to intervention, 2) percutaneous transluminal angioplasty (PTA) was our first choice for main trunk disease, 3) surgery revascularization or autotransplant in patients where PTA fails and for those beyond the first bifurcation intrarenally involving branched arteries stenosis, 4) removal of a completely atrophic dysfunctional kidney with high renal vein plasma renin activity or 5) a combination of PTA and surgery. Statistical Analysis Data were described as frequencies, medians with ranges and means with standard deviation (SD), as appropriate. Two-by-two contingency tables were analyzed using the chi-square test or in the case of small numbers, Fisher’s exact test. P<0.05 was set as the level of statistical significance. RESULTS Medical records were reviewed from a consecutive series of 45 hypertensive children (16 RVH and 29 non-RVH), 17 females and 28 males (Table 1). The mean age of the population was 14.7 +/- 3.78 years (range from 2-18 years). Twenty-eight patients were Caucasian, while 17 were afro-Caribbean. The duration of known hypertension was 21.5 +/- 26.6 months (ranging from 1-120 months). At the time of their first medical visit, blood pressure (BP) was 163.9 +/- 21.7 mmHg for systolic and 115.4 +/-20.8 mmHg for diastolic. Almost all patients had a few symptoms (headache, palpitation, flushing, etc). Mean serum creatinine level was 0.86 +/- 0.20 mg/dL and mean plasma renin activity was 7.6 +/- 6.4 ng/ml/hr. Captopril-stimulated plasma renin activity tests were positive in 63% (76% in RVH and 52% no-RVH) (p<0.05) of children in which they were performed. In our series, basal and post-captopril scintigraphy was positive in 69.2% of RVH cases, and in only 23.5% of non-RVH patients (p<0.05). Non-statistical significance level was found between RVH and non-RVH patients in age, sex, gender, mean systolic blood pressure, mean serum creatinine plasma activity and measurement of renal vein renin levels. Statistical significance (p<0.05) was found in time of known hypertension, diastolic blood pressure, Captopril scintigraphy test and Captopril plasma renin activity test. (Table 1). Digital subtraction arteriography demonstrated 16 renal artery stenosis (35.6%), 11 unilateral (24.5%) and 5 bilateral (11.1%), four cases of longitudinal narrowing renal artery (8.9%) without a specific stenosis with a reduced kidney size (atrophic or hypoplasia), one case (2.2%) with renal angioma, one arteriography (2.2%) which was not useful in defining artery disease for technical reasons, and in 23 patients (51.1%), the study was normal. Extra renal lesions (aorta, mesenteric or cerebral) were not found, although no systematic study was done for this purpose. Table 1: Baseline Clinical and Laboratory Findings in 45 Hypertensive Patients Aged 2-18 Years, Institute of Nephrology, Havana, (1986 – 2001)
*p<0.05 The etiology of hypertension in our series was: renovascular hypertension (artery stenosis >60%) 16 cases (35.6%) and non-RVH 29 patients (64.4%). Non-RVH etiologies: four cases related to longitudinal narrowing renal artery without stenosis with a reduce kidney size (8.9%), 1 patient with renal angioma (2.2%) an in other 29 patients (53.3%), non-other causes of secondary hypertension were not identified (essential hypertension). Once the diagnosis was established, three therapeutic modalities were chosen: medical therapy with antihypertensive drugs (28 non-RVH patients), PTA (10 RVH patients) and surgery (seven cases - 6 RVH and one non-RVH patient). Percutaneous transluminal angioplasty or surgery was used in 17 patients (37.8%) - 16 RVH and one non-RVH. PTA (without stent placement, our first choice) was performed in eight cases (17.8%), six unilateral and two bilateral. PTA plus surgery (PTA and autotransplant in a bilateral stenosis case and one nephrectomy after PTA artery thrombosis) was used in two cases (4.4%) and a surgical procedure alone (four nephrectomy in completely atrophic dysfunctional kidney with main branch artery stenosis, a nephrectomy in one non-RVH patient with an atrophic kidney, one pheochromocytoma resection in the renal hilium with direct arterial compression and one partial nephrectomy for an angioma), was used in the remaining seven patients (15.6%). Twenty-eight non-RVH patients (62.2%), received medical treatment only (beta blocker, calcium antagonist, ACE-inhibitors and diuretics). We avoid the use of ACE-inhibitors or antagonist receptors of angiotensin in RVH patients because they can induce renal dysfunction in cases with bilateral stenosis or in a solitary functioning kidney. At the end of the follow-up period, 43 patients (95.6%) were normotensive, 14 (31.1%) of them without the use of antihypertensives and 29 (64.5%) with antihypertensive drugs. Two children (4.4%) were lost to follow-up. (Table 2). Of the 16 RVH patients, 12 (75%) were normotensive without antihypertensive drugs after PTA or nephrectomy. In three (18.75%), BP was normal but needed some drug support and one case was lost of follow-up. Table 2: Blood Pressure Control With Various Treatment Modalities in 45 Hypertensive Children
In all cases treated with a surgical procedure, complete control of the BP was obtained (five RVH and two non-RVH patients). PTA alone in RVH patients was successful in eight cases; in two other cases, it was successful when combined with surgery (one autotransplant and one nephrectomy). In seven patients (70%), the high blood pressure was cured, while three patients (30%), required some form of medication to control blood pressure, albeit in a small dosage. Mean serum creatinine levels were maintained within normal limits during all follow-up periods. The only case with abnormal basal serum creatinine and treated with antihypertensives was stable after five years of follow-up. There was not mortality in the study. Renovascular Hypertension Patients In this study, 16 patients, 10 males (62.5%) and 6 females (37.5%) were identified as having RVH secondary to renal artery stenosis, 11 unilateral (68.7%) and five bilateral (31.3%) (Table 1). The prevalence of RVH in our series is 35.6%. Fibromuscular dysplasia accounted for 11 cases (68.7%), and the etiology of the other cases was: three arteritis (18.7%), one hilium pheochromocytoma with direct arterial compression (6.3%) and one unclassified arterial disease (arteritis?) (6.3%). Ten of these cases were treated by PTA. In eight patients, PTA alone without stent was employed (median age 14.8 years, six with unilateral stenosis). Blood pressure was normalized in five patients (62.5%), and improved in three (37.5%) with drugs, albeit in a small dose, in the five years of follow-up. In two children, PTA was combined with surgery, one boy (age 14 with bilateral stenosis), underwent an autotransplant and one girl (age 15 with an unilateral stenosis), underwent a nephrectomy after total renal artery obstruction one year after PTA. A nephrectomy of a small atrophic dysfunctional kidney with main artery stenosis and unilateral plasma renin production was performed in five children (median age 12.5 years old) and a hilium pheochromocytoma resection in a patient with direct arterial compression. The results of long-term follow-up for those children treated with surgical procedures were excellent, hypertension was cured and kidney function was preserved in all cases. Mean serum creatinine levels were within normal limits during all follow-up periods. Discussion The underlying causes of significant hypertension in the pediatric population differ considerably from those of adults. While the prevalence of hypertension in children is lower than adults, secondary hypertension is more frequent, with children accounting for 75%-80% of cases.[3,5,6] The most frequent causes during adolescence and childhood include renal parenchyma diseases and renal artery stenosis as major causes of elevated diastolic pressure. In the last 15 years of a screening program for RVH detection in a selected group of hypertensive children with one or more clinical suspicious signs, 16 patients (35.6%) were diagnosed as having RVH. Renovascular hypertensive patients were younger than non-RVH patients, but without statistical significance (mean age 13.94 +- 3.92/15.04 +-3.72 years old), although gender and race distribution was similar in both groups.[16] The mean BP in our patients was moderate/severely elevated, especially mean diastolic blood pressure (p<0.012) in RVH cases in which two patients presented hypertensive encephalopathy as the first sign of their arterial hypertensive disease. In general, only a small percentage of patients were symptomatic at the beginning of the study, as has been reported elsewhere.[7,16] The majority of the children had elevated plasma renin activity, especially in RVH patients, but no statistical significance level between RVH and non-RVH patients was found. Renal vein renin ratio levels were not useful in our series in predicting a positive response to revascularization since the number of tests was too small or failed to demonstrate lateralization in the presence of hemodynamically significant renal artery stenosis for several reasons (errors in technique, dilution of renal blood, bilateral stenosis, vascular damage secondary to hypertension, etc). The utility of non-invasive imaging tests has not been well studied in children, although some established guidelines for the application of this test are available.[17,18] In experienced centers, the combination of different tests shows adequate correlations with renal arteriography and provides evidence for therapy procedures results.[14,16-18] In our series, the captopril-stimulated plasma renin test (positive response 76% in RVH and 52% in non-RVH patients, p<0.05), and captopril scintigraphy, correlated with arteriography (positive test 69.2% in RVH and 23.5% in non-RVH patients, p<0.01), both with statistical significance levels; showed a sensitivity (75% and 76.9%), specificity (52.9% and 76.4%); and predicted value for the presence of renal artery stenosis (96.5% and 76.6%) respectively. In experienced centers, the combination of both tests shows a high sensitivity and specificity in identifying patients with clinical suspicion of RVH, evaluating the efficacy of revascularization procedures, and in providing a BP prediction response to PTA or surgery.[5] This series, albeit small, suggests that both tests could be useful for therapeutic decision and prognosis, although it could be explained by small, intra-renal artery pathology not found in our cases where selective renal arteriography pre- and post-revascularization was performed. Other imaging tests like spiral CT angiography (CTA) and magnetic resonance angiography (MRA), can be useful for diagnostic purposes in selected cases, but should not be used for screening purposes in patients with moderate clinical suspicious of RVH due to cost/affectivity, large radiation exposure, and the large quantities of contrast medium in CTA and MRA, which only recognize main artery abnormalities. These non-invasive diagnostic procedures correlate strongly with arteriography. Both technologies were not available for many years in our service.[19] Additional investigative techniques such as Doppler ultrasonography, is mainly utilized in adults and there is limited data in children.[5,16] Renal arteriography remains the gold standard radiological test in the diagnosis and treatment of RVH. This study gives us the exact location of the disease, helps in determining the etiology in most cases and also gives us adequate information in reference to the extension of the arterial lesion.[7,9,10,16,20] The most common cause of RVH disease in children is fibromuscular dysplasia.[5.6,7,9,19] The most frequent etiology of RVH in our series was fibromuscular dysplasia, accounting for 68.7% of patients – a figure similar to one reported in Broekhuizen-de Gast HS et al.[6], and in higher prevalence than that seen in the study by Estepa R. et al.[5], McTaggart SJ et al.[7] and Chalmers RT et al.[10] The aims of the treatment modalities, medical treatment, PTA and surgery, were the control of arterial blood pressure and the preservation of renal function. The loss of renal function in RVH can be secondary to either a complication of invasive manipulation of the renal artery, or as a consequence of a progressive narrowing of the native renal artery. Adequate diagnosis is especially critical in children where the stenosis is often bilateral; this was found in 11% of our patients (31% of RVH patients). A significant stenosis carries the risk of long-term loss of renal mass function, although these changes can occur with fibromuscular dysplasia as well. However, total occlusion and renal failure are rare events in children. On the other hand, a very important factor to take into consideration is that the rate of progression after operative intervention can be delayed in some patients. The rate of renal artery restenosis after PTA has been reported to be higher in some cases than in patients who have had their diseased vessel left intact. These observations are thought to be due to an accelerated thrombosis and/or neointimal formation resulting from post-PTA vascular injury.[7,10,16] This is one reason why in children, any invasive non-surgical intervention is controversial. However, most children benefit from these interventional procedures.[7,10,20] In our series, PTA was indicated in ten patients (in two children, PTA was combined with surgery, one boy underwent an autotransplant and one girl underwent a nephrectomy after renal obstruction one year after PTA) with median age 14.8 years. All PTA patients remain normotensive, seven without drugs and three with drugs, albeit in a small dosage. Surgical management was indicated in seven patients, four nephrectomy of a small atrophic, with main renal artery stenosis and dysfunctional kidney, one nephrectomy in a non-RVH patient with longitudinal narrowing renal artery (with a atrophic kidney with unilateral plasma renin production), one hilium pheochromocytoma resection and one polar nephrectomy for an angioma in a non-artery stenotic-RVH patient. Hypertension was cured in all surgical cases. Comparing therapeutic results, those of our patients who underwent surgery had better outcomes than those treated by PTA, but our number of patients is too small to bring statistical results. We conclude that it’s possible to find a high prevalence of RVH in any population of hypertensive children with suspicious clinical signs and that renal arteriography must be included in their work-up in order to make a proper and timely diagnosis and treatment. Non-invasive tests such as captopril-stimulated plasma rennin and captopril scintigraphy are useful for diagnosis and therapeutic decisions, although renal angiography remains the gold standard radiological procedure for accurate evaluation, diagnosis and treatment. PTA, surgery or a combination of PTA and surgery in patients with RVH, controls arterial blood pressure in the majority of patients and subsequently preserves their renal function. REFRENCES
THE AUTHORS
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