- Email: [email protected]
Renal Hypertension in Children
Symposium on Pediatric Nephrology
Renal Hypertension in Children David L. Olson, M.D., * and Ellin Lieberman, M.D. t
Hypertension is increasingly being recognized in individuals less than 20 years of age. Although primary or essential hypertension occurs in children, a secondary cause for high blood pressure may be found in 75 to 80 per cent of pediatric patients with hypertension. The most frequent is renal disease. Information concerning renal hypertension in children is sparse and is generally confined to reports of specific conditions rather than a description or an analysis of all forms of renal hypertension. A registry of children with hypertension was started at Children's Hospital of Los Angeles (CHLA) in order to build a data base. Retrospective and prospective analysis of records of 110 patients with renal hypertension who were diagnosed from 1970 to 1975 in five Los Angeles hospitals (85 from CHLA) was carried out. All patients with documented renal hypertension were included except for patients who could not be diagnosed, patients with systemic lupus erythematosus, and patients who developed hypertension after hemodialysis or renal transplantation. Data were collected by trained data management technicians after coding forms had been devised and pretested, and collated by electronic data processing. This review presents the available preliminary information concerning these 110 patients. Gaps in the coding and availability of information have been identified. Where quantitative information is incomplete, qualitative approaches have been substituted. Frequency distribution by diagnosis, age, and sex of 110 patients with renal hypertension is presented in Table 1. The nine diagnostic categories were derived from the data and from the experience of the attending nephrologist.
Symptoms Associated with Renal Hypertension Information concerning 28 specific presenting symptoms was coded in the registry. No symptom occurred in a frequency of 50 per cent or *Assistant Professor of Pediatrics, University of Southern California School of Medicine, Los Angeles, California
t Professor of PediatriCS, University of Southern California School of Medicine; Head, Division of Nephrology, Children's Hospital of Los Angeles, California Supported by the California Regional Medical Programs, Contract ROP-75G-513-0-147P (111174 to 6/30/76) Pediatric Clinics of North America-Vol. 23, No.4, November 1976
795
796
DAVID L. OLSON AND ELLIN LIEBERMAN
Table 1. Registry of 110 Patients with Renal Hypertension (1970 to 1975) SEX NO. OF
AGE RANGE
MEDIAN AGE
(Years)
(Years)
DIAGNOSIS
PATIENTS
Male
Female
Acquired renal parenchymal disease (hemolytic uremic syndrome, renal trauma, nephrotic syndrome, chronic pyelonephritis) Acute glomerulonephritis Congenital malformations Nonurologic (infantile polycystic disease, bilateral renal hypoplasia, solitary cyst) Urologic (vesicoureteral reflux, obstructive uropathy, neurogenic bladder, exstrophy of bladder) Progressive renal parenchymal disease" Nonurologic (membranoproliferative glomerulonephritis, focal glomerulosclerosis, chronic glomerulonephritis) Urologic (chronic nonobstructive pyelonephritis, obstructive uropathy) Renovascular hypertensiont End stage renal disease Other
34
12
22
.3-18
9.5
21
16
5
2-14
7.5
15
4
11
.1-17
1.0
5
4
1
.3-16.5
9
4
5
.2-17
7.0
5
4
.4-16.5
9.0
11
4
7
.3-11
5.0
4 4
.1-17.5 .5-17
5 5
13
9.0 13.5
*Increasing clinical and laboratory evidence of renal failure but no end-stage renal disease (GFR < 10 ml/min/1. 73 M2). tDefined as angiographically demonstrated main or segmental renal artery stenosis.
greaterin this series and only those symptoms which appeared in 10 to 30 per cent are included in Table 2. Data were further analyzed to exclude symptoms of 21 children with acute glomerulonephritis to determine if their data might have skewed the findings. The data listed for these seven symptoms, both for the entire group and for the remainder without acute glomerulonephritis, suggest that these symptoms are representative of both acute and chronic renal disorders in the pediatric age group and that symptoms usually ascribed to acute glomerulonephritis can be expected in other acute and chronic renal diseases. The expected frequency of well known symptoms associated with chronic and/or progressive renal failure, such as fatigue, lethargy, failure to thrive, or perceptible change in growth velocity, was not found in 19 patients with compromised renal function. This discrepancy may be explained by the fact that the data coded represent a compilation of the admitting histories and physical
797
RENAL HYPERTENSION IN CHILDREN
Table 2. Presenting Symptoms of Renal Hypertension in 110 Patients as Compared with Symptoms in 89 Patients Without Acute Nephritis WHOLE GROUP eN SYMPTOM
Swelling Headache Nausea/vomiting Fever Poor appetite Fatigue Dizziness
= 110)
WITHOUT NEPHRITIS eN
= 89)
No. of Patients
Per Cent
No. of Patients
Per cent
34 33 30 18 17 12 10
31 30 27 16 15 11 9
18 24 20 9 11 11 10
20 27 22 10 12 12 11
examinations by medical students, interns, residents, and attending physicians; it remains uncertain whether complaints suggestive of chronic renal failure did not exist in this sample or whether historical information relating to these symptoms was missing.
Physical Findings Seventeen variables, other than hypertension, relating to cardiovascular findings, fundoscopic abnormalities, organomegaly, edema, and bruit were sought as part ofthe coding for positive physical findings at the time of initial evaluation. Only those findings with a frequency greater than 10 per cent have been included. While heart murmur was listed in 42 of 110 patients (38 per cent), preliminary review of the data indicate that murmur was included without commentary as to its significance. Arteriolar narrowing was found on examination of the optic fundi in 15 per cent of the patients; retinal hemorrhage, exudates, and papilledema were not recorded. Peripheral edema, hepatomegaly, rales, and increased heart size, noted in from 10 to 25 per cent of the patients, might have been anticipated in a group of children with various types of renal hypertension. The listing of "hepatomegaly" did not require a description of measurement of liver size and the 20 patients with hepatomegaly include children with acute glomerulonephritis, hemolytic uremic syndrome, and infantile polycystic disease of the kidney. Data concerning typical physical findings of chronic renal failure were not included in the registry. Nevertheless, the signs which reflect diminished glomerular filtration rate and ultimately become reflected in Table 3. Physical Findings in 110 Patients with Renal Hypertension
Heart murmur Peripheral edema Hepatomegaly Retinal arteriolar narrowing Rales Increased heart size
NO. OF PATIENTS
PER CENT
42 28 20 17 11 11
38 25 18 15 10 10
798
DAVID L. OLSON AND ELLIN LIEBERMAN
the clinical syndrome of uremia should be sought in hypertensive children. These signs are protein calorie malnutrition, uremic odor, sallow complexion, osteodystrophy, pruritus, metastatic calcification, central nervous system disturbances, peripheral neuropathy, pericarditis or pneumonitis. Diagnosis The simplest way to approach the differential diagnosis of renal hypertension is to separate disorders associated with acute hypertension (often reversible) from those associated with chronic hypertension. Children with acute renal hypertension classically present with a history of prior good health followed by the abrupt emergence of signs and symptoms reflecting renal disease, for example, change in urinary habits, decreased urine output, or gross hematuria. Headache, nausea, and vomiting are common. Physical examination does not reveal evidence of longstanding severe or malignant hypertension such as facial palsy, hypertensive retinopathy (hemorrhages, exudates, papilledema) or cardiomegaly due to left ventricular hypertrophy. Rash, fever, or costovertebral angle tenderness may suggest more specific causes of acute disease. In contrast to chronic or end-stage renal failure, pallor, growth failure, osteodystrophy, and other signs of uremia are absent in patients with acute renal hypertension. Laboratory findings which may be useful in differentiating conditions associated with acute or chronic hypertension are summarized in Table 4. This table is idealized to convey patterns of laboratory findings, and it must be borne in mind that exceptions exist. The registry data did not permit analysis oflaboratory results, and these data will be presented in subsequent publications. The most common causes of hypertension secondary to acute renal disorders are acute glomerulonephritis, anaphylactoid purpura, and hemolytic uremic syndrome. Chronic hypertension may result from renovascular or renal parenchymal disease. One special group of patients with renal parenchymal disease is that with asymmetric disease, i.e., a unilateral small kidney. These two groups (renovascular and asymmetric renal parenchymal) are Table 4. Laboratory Studies in Patients with Renal Hypertension CHRONIC
Urinalysis HemoglobinJhematocrit Blood chemistries BUN/creatinine Calcium Phosphorus Alkaline phosphatase Other studies Electrocardiogram Chest x-ray: heart size X-ray: osteodystrophy
ACUTE
Parenchymal
+
+
Normal
t
Normalor Normal or Normal
t t
Normal or LvH Normal or t
Renovascular
t
Normal
t t t t
Not always normal Normal Normal Normal
Normal or LVH Normal or t
+
LvH
t
RENAL HYPERTENSION IN CHILDREN
799
important because hypertension in affected children may be cured by surgery. Because these conditions are relatively rare and many special investigative studies have been developed only during the past decade, descriptions of clinical and laboratory findings in such pediatric patients are not available. Some information, however, has been collected from a retrospective-prospective survey of a group of patients with renovascular or renal parenchymal hypertension at CHLA. These data are not completely integrated into the registry and therefore cannot be presented in tabular form. . These patients presented with moderate to severe hypertension from infancy through childhood. Both sexes were equally affected. The children with renovascular disease (unilateral or bilateral major renal artery or segmental renal artery stenosis) all had normal urinalyses and renal function studies; those with asymmetric renal parenchymal disease were more likely to have abnormal urinalyses and slight elevations in determinations of BUN or serum creatinine. Intravenous pyelography or renal scintigraphy and renograms identified those patients with hypertension secondary to unilateral renal parenchymal disease. Rapid sequence intravenous pyelogram, renal scintigraphy, renogram, and measurement of peripheral renin activity have been used extensively in hypertensive adults to identify those with renovascular disease. 1. 4. 5 Findings on RIVP which indicate that renal artery stenosis may be present in adults include a discrepancy in size of 1.5 cm or greater between the two kidneys, differences in the appearance, concentration, and excretion of contrast, and the presence of ureteral notching (implying the existence of arterial collateral circulation). Positive findings on renal scintigraphy and on renograms using 131I-hippurate which suggest major renal artery stenosis include a disparity of greater than 10 per cent of isotopic counts between the two kidneys and significant differences in the curves on the renogram which reflect the vascular phase, concentration, and excretion of the isotope by the two kidneys. Peripheral renin activity is elevated in the majority of adults with renovascular hypertension. 8, 9 Renal angiography, however, remains the definitive diagnostic test. Comparative data for children have not been published. Measurement of renin activity in the renal veins has been used to identify patients with unilateral renal disease causing hypertension and to predict surgical curability.7-9 If the renal vein renin ratio exceeds 1.5, indicating that the diseased kidney is secreting at least 50 per cent more renin than the contralateral kidney, a revascularization procedure or unilateral nephrectomy has been associated with cure of hypertension in approximately 80 per cent of adults with unilateral renal disease. 8 Data to evaluate the usefulness of this test in children with renal hypertension are inadequate. In the group of children with renovascular hypertension at CHLA the following results were found: rapid sequence intravenous pyelogram was suggestive of renovascular disease in less than 50 per cent, increased plasma renin activity was found in the majority of children, and renal scintigraphy and renograms using 131I-hippurate were positively correlated with the results of renal angiography in 64 per cent. The renal vein renin ratio exceeded 1. 5 in 6 patients and 3 of these patients underwent surgery with cure of hypertension in 2 of the 3. These data suggest that
800
DAVID L. OLSON AND ELLIN LIEBERMAN
measurement of plasma renin activity, renal scintigraphy and renograms, and rapid sequence intravenous pyelograms are useful screening tests, but definitive diagnosis rests with renal angiography. More experience must be accumulated to assess the utility of renal vein renin ratios in predicting surgical curability of renovascular hypertension in children. Intravenous pyelography and renal scintigraphy identified all patients at CHLA with hypertension caused by asymmetric renal parenchymal disease, and plasma renin activity was elevated in every patient in whom it was measured. Unilateral nephrectomy was done in two patients after the renal vein renin ratio was found to exceed 1.5. This procedure resulted in cure of hypertension in one patient with an angiographically normal contralateral kidney and resulted in failure in the second patient with an angiographically abnormal contralateral kidney.
Chronic Renal Parenchymal Hypertension The suspicion that a child may have progressive renal insufficiency, chronic renal insufficiency, or end-stage renal disease evolves readily from a review of the history, physical examination, and analysis of unsophisticated laboratory results. These children characteristically have often been regarded as sickly throughout their lives or from some indeterminate time, do not grow well, and are usually unable to keep pace with their peers physically, emotionally, or intellectually. Physical findings may range from a few signs-i.e., pallor, poor growth, presence or absence of renal masses-to the full blown picture of uremia. Laboratory confirmation of renal functional impairment confirms the diagnosis of chronic renal disease. Following this analysis, the most important questions are: Is any abnormal component of the child's clinical status reversible? Is there a specific diagnosis for which specific therapy is indicated? What is optimal comprehensive therapy?
Treatment Conditions which may be cured by surgical intervention include major or segmental renal artery stenosis, potentially curable by revascularization procedures and unilateral renal parenchymal diseases such as renal hypoplasia, chronic pyelonephritis, unilateral renal trauma, and unilateral ureteral obstruction, potentially curable by nephrectomy or relief of obstruction. If hypertension is not of long duration and the contralateral kidney is not irreversibly damaged by hypertension per se, surgical procedures on the affected kidney may result in permanent cure, defined as normal blood pressure for sex and age without medication in a child who has normal renal function which can support growth until physical maturity is achieved. Surgical failure may be due to technical errors, inappropriate selection criteria, inadequate evaluation of renal function and of the contralateral kidney, lack of lateralization of renal vein renin ratios (i.e., < 1.5), and incorrect diagnosis. A program of medical therapy must then be developed. The development of a medical treatment plan must take into account the duration and severity of hypertension. Ajudgment must be reached as to whether hypertension is acute and therefore likely to respond to relatively low doses of mild antihypertensive agents, or chronic and likely to be more resistant. Knowledge of the specific disease and insight into the
RENAL HYPERTENSION IN CHILDREN
801
pathogenesis of hypertension permit the physician to develop a rationale for the use of diuretics, vasodilators, inhibitors of renin secretion, or drugs which act by their influence upon the sympathetic nervous system. For example, evidence accumulated from studies of body composition in experimental animals and adults suggests that hypertension associated with renal parenchymal disease is attended by expansion of extracellular fluid volume and/or plasma volume;lO diuretic therapy in this situation would seem to be the most logical first step. Other factors related to the pathogenesis of renal hypertension include the renin-angiotensin system and its relationship to the autonomic nervous system (especially through the sympathetic innervation of the juxtaglomerular apparatus which influences renin release) and circulating levels of plasma catecholamines which are potent vasoconstrictors. These and other factors have not been investigated in children with various types of renal hypertension. Another important consideration in the choice, route, and dosage of antihypertensive drugs is an assessment of renal function. Is the serum creatinine elevated solely because of reduced glomerular filtration due to glomerular inflammatory changes, necrosis, and scarring of glomerular structures and fibrin deposition? Or does the creatinine elevation reflect arteriolar constriction leading to hypertension and reduction of glomerular filtration rate? Or, are the two phenomena combined so that it is not possible to determine the relative contribution of each? The majority of diuretic and antihypertensive agents have been available long enough to accumulate data and experience. However, because of the complexity of designing clinical protocols and the restraints imposed concerning the use of these agents in children, very little information has been published concerning their effectiveness (except in short-term trials) in conditions other than acute glomerulonephritis. Studies concerning the short-term effectiveness of furosemide 6 and diazoxide 3 in acute nephritis are available and an article on sodium nitroprusside has been published recently.2 Accordingly, the recommendations presented below are based on experience at CHLA and have not been subjected to critical analysis. An empirical schema for a stepwise approach to treatment of hypertension is presented in Figure 1 and reflects both the current practice at CHLA and general recommendations for adults with essential and renal hypertension. Therapy is usually initiated (except in hypertensive emergencies) with a thiazide diuretic. If diuretic therapy does not provide adequate blood pressure control, hydralazine or methyldopa is added (Fig. 1, Step II). The dose of either agent is increased until blood pressure control is achieved or until significant side effects occur. Relatively common side effects of hydralazine include headache, nausea, and vomiting, and common side effects of methyldopa are lethargy and decreased mentation. These side effects often disappear a few days after initiation of therapy or after increasing the dose, but persistence may necessitate decreasing the dose or stopping the drug altogether. Rare side effects of methyldopa include hemolytic anemia and hepatocellular disease, and a rare complication of hydralazine therapy is a lupus-like syndrome with or without a positive antinuclear antibody test. At CHLA a positive antinuclear antibody test has been encountered rarely and only when large doses of hydralazine (Le., 200 mg daily in adolescents) have been used for long
802
DAVID
L.
OLSON AND ELLIN LIEBERMAN
HYPERTENSION
I
I Medical I Dietary Therapy Sodium Calories
Surgical
~Cure
Noncure
Pharmacologic Therapy }
Mild Hypertension
)
Mild to Moderate Hypertension
STEP I
Diuretics
~
HYdralaWYldopa
Triple Therapy
)
Moderate and/or Resi slant Hypertension
STEP 11
STEP III
Guanethidine
Chronic Hypertension r - - - - - - or - - - - - - - ,
Diozoxide or Furosemide
Nitroprusside
Hypertensive Emergency
STEP IV
Figure 1. An empirical schema for treatment of renal hypertension is depicted.
periods (over 3 months). Hydralazine-induced lupus syndrome has not developed in any child or adolescent during the past 10 years at CHLA. If a combination of two agents is ineffective in achieving blood pressure control, combined therapy with a thiazide diuretic, methyldopa, and hydralazine is recommended (Fig. 1, Step III). A more potent diuretic, such as furosemide, may be substituted for the thiazide. Iftriple therapy is required, however, it constitutes a signal that one or more ofthe following factors should be assessed: (1) Is the patient taking the medication? (2) Is the present medication prescribed in dosages and at times which provide maximal therapeutic effectiveness? (3) Has a superimposed event which may exacerbate hypertension (such as acute hydronephrosis or an emotional crisis) taken place? (4) Has the patient inadvertently received agents with pressor effects, such as corticosteroids, sympathomimetics, or oral contraceptives with estrogens? (5) Is the patient ingesting excessive amounts of sodium in the form ofN aCI or food preservatives? Once it is ascertained that the above factors are not creating "resistant" hypertension, then triple therapy may be used. As an alternative to therapy with these three agents for moderate to severe hypertension, guanethidine may be used. The experience with guanethidine is limited in pediatrics and it may cause orthostatic hypotension. Guanethidine should be reserved for patients who are unresponsive to more conservative therapy.
RENAL HYPERTENSION IN CHILDREN
803
Intravenous diazoxide is used for treatment of hypertensive emergencies (Fig. 1, Step IV), defined as blood pressure of 200 mm Hg systolic, 140 diastolic, or greater (regardless of age), usually in a patient with chronic hypertension (except in the setting of dialysis or renal transplantation) and with evidence of target organ involvement (i.e., hypertensive retinopathy, seizures, facial palsy, cardiomegaly or congestive heart failure). Diazoxide is given by rapid bolus intravenous injection, avoiding extravasation with subsequent necrosis of surrounding tissues. An antihypertensive effect may be expected within minutes and no later than one hour if the drug has been administered correctly; a repeat dose should not be given until 60 minutes have elapsed because of the possibility of causing hypotension. Because diazoxide is such a potent vasodilator, it is a powerful antihypertensive agent and is usually not needed for the treatment of hypertension in acute renal disorders such as acute glomerulonephritis. Intravenous furosemide (1 to 2 mg/kg) is needed to counteract the salt and water retaining properties of diazoxide. After control of severe hypertension has been achieved with diazoxide, agents such as methyldopa, hydralazine, and diuretics may be instituted to maintain blood pressure control. The experience with sodium nitroprusside in hypertensive emergencies is very limited in pediatrics. At CHLA this agent has been used in the rare instance when diazoxide has failed to control hypertension and in one instance when repeated administration of diazoxide led to severe hyperglycemia and elevation of the serum amylase. Sodium nitroprusside is given by continuous intravenous infusion starting with a dose of 0.5 mcg/kg/minute and increasing to a maximum of 5 mcg/kg/minute. Its onset of action is immediate and the dose must be titrated with the physician in attendance. Side effects include thiocyanate toxicity (nitroprusside is metabolized to thiocyanate) and hypothyroidism. In small children nitroprusside has rarely been used, and its use must be limited to only a few days. Outcome Outcome of treatment in 100 of 110 registry patients with renal hypertension is presented in Table 5. Ten patients, those with end-stage renal disease and those with miscellaneous conditions, were excluded from this analysis. These categories included patients with the most severe hypertension and with progressive decrease in renal function; adequate blood pressure control was most difficult to achieve in these patients who constitute a critical group because the majority will eventually enter dialysis and transplant programs in which the patient's course may be complicated by severe hypertension and target organ damage. Three of 11 patients with renovascular hypertension underwent surgical correction with subsequent cure. Seven of these are on medical therapy and remain mildly hypertensive. Patients with abnormal blood pressure values without therapy have mild hypertension which is considered not sufficiently elevated to treat or is resolving. Summary Preliminary results of this retrospective-prospective analysis of renal hypertension in 110 children indicate that hypertension may be secondary
804
DAVID
L.
OLSON AND ELLIN LIEBERMAN
Table 5. Outcome in 100 Patients with Renal Hypertension
Acquired renal parenchymal disease Acute glomerulonephritis Congenital malformations (urologic/nonurologic) Renovascular hypertension Progressive renal parenchymal disease (urologic/nonurologic) TOTAL
ABNORMAL BLOOD
PRESSURE
PRESSURE
Without Therapy
With Therapy
Without Therapy
With Therapy
Expired
34
14
7
2
11
0
21
13
20
4
3
5
2
11
3
0
7
0
14 100
4 38
11
7 31
0 3
NO. OF DIAGNOSIS
NORMAL BLOOD
PATIENTS
5
6
2 17
to a wide variety of acute, progressive, and chronic renal diseases which may be either congenital or acquired. Affected children may be detected at any time from infancy through adolescence. Symptoms usually associated with acute glomerulonephritis (Le., headache, swelling, nausea, vomiting, anorexia, fatigue, dizziness, and fever) occur in both acute and chronic renal diseases associated with hypertension. Headache and swelling are the most common symptoms in this series. Peripheral edema, rales, and increased heart size were found in between 10 and 25 per cent of these children. Differential diagnosis may be approached by a consideration of causes of acute and chronic hypertension. The child with chronic renal disease usually presents with a long history of fatigability, poor growth, and pallor, and laboratory tests reveal elevation of the creatinine and B UN along with anemia, hypocalcemia, and hyperphosphatemia. In contrast, the child with acute renal disease and hypertension presents with a history of prior good health followed by the abrupt onset of signs and symptoms of renal disease; laboratory tests usually reveal modest elevations of creatinine and BUN, anemia is unusual, an abnormal urinalysis is common, and serum calcium and phosphorus levels are usually normal. Renovascular and asymmetric renal parenchymal disease represent uncommon but important conditions because surgery may be curative. Treatment may be surgical, medical, or combined. Surgical conditions include renal trauma, hydronephrosis, asymmetric renal disease, and renal arterial disease. Adequate blood pressure control without medication can be expected following surgery in instances of unilateral involvement with a normal contralateral kidney. Meticulous assessment of the contralateral kidney is needed to determine that it is normal. If surgery is unsuccessful or is not indicated, pharmacologic therapy is
RENAL HYPERTENSION IN CHILDREN
805
initiated with a stepwise regimen starting with the mildest agent (e.g., thiazides) and then adding additional antihypertensive drugs when adequate blood pressure control has not yet been achieved. The goal of therapy is the lowest, safest, tolerated blood pressure levels. Long-term, carefully designed studies of antihypertensive agents for children with renal hypertension are not available. The need for collection and critical analysis of data concerning the clinical course of children with renal hypertension is evident from a review of the literature and from the preliminary data presented in this series. The presentation of such information and a critique of outcome variables will provide a basis for program planning for affected children and improvement in patient care where indicated.
REFERENCES 1. Bookstein, J. J., Abrams, H. L., Buenger, R. E., et al.: Radiologic aspects of renovascular
2. 3. 4. 5. 6. 7. 8. 9. 10.
hypertension. Part 2. The role of urography in unilateral renovascular disease. J.A.M.A., 220:1225, 1972. Gordillo-Paniagua, G., Velasquez-Jones, L., Martini, R., et aI.: Sodium nitroprusside treatment of severe arterial hypertension in children. J. Pediat., 87:799,1975. Kohaut, E. C., Wilson, C. J., and Hill, L. L.: Intravenous diazoxide in acute poststreptococcal glomerulonephritis. J. Pediat., 87:795, 1975. Maxwell, M. H., Lupu, A. N., and Taplin, G. V.: Radioisotope renogram in renal arterial hypertension. J. UroI., 100:376,1968. Quinones, J. D., Varma, V., and Macal, 0.: Radionuclide and pyelographic tests in screening for renovascular hypertension. Arch. Intern. Med., 129:570, 1972. Repetto, H. A., Lewy, J. E., Brando, J. L., et al.: The renal functional response to furosemide in children with acute glomerulonephritis. J. Pediat., 80:660, 1972. Schambelan. M., Glickman, M., Stockigt, J. R., et al.: Selective renal-vein renin sampling in hypertensive patients with segmented renal lesions. New Engl. J. Med., 290:1153, 1974. Stockigt, J. R., Noakes, C. A., CollinS, R. D., et al.: Renal vein renin in various forms of renal hypertension. Lancet, 1 :1194, 1972. Vaughan, E. D., Buhler, F. R., Laragh, J. H., et al.: Renovascular hypertension: Renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow and score for surgical curability. Am. J. Med., 55:402, 1973. Vaughan, E. D., Buhler, F. R., Laragh, J. H., et al.: Hypertension and unilateral parenchymal renal disease. Evidence for abnormal vasoconstriction-volume interaction. J.A.M.A., 233:1177,1975.
Division of Nephrology Childrens Hospital of Los Angeles Box 54700, Terminal Annex Los Angeles, California 90054
Renal Hypertension in Children David L. Olson, M.D., * and Ellin Lieberman, M.D. t
Hypertension is increasingly being recognized in individuals less than 20 years of age. Although primary or essential hypertension occurs in children, a secondary cause for high blood pressure may be found in 75 to 80 per cent of pediatric patients with hypertension. The most frequent is renal disease. Information concerning renal hypertension in children is sparse and is generally confined to reports of specific conditions rather than a description or an analysis of all forms of renal hypertension. A registry of children with hypertension was started at Children's Hospital of Los Angeles (CHLA) in order to build a data base. Retrospective and prospective analysis of records of 110 patients with renal hypertension who were diagnosed from 1970 to 1975 in five Los Angeles hospitals (85 from CHLA) was carried out. All patients with documented renal hypertension were included except for patients who could not be diagnosed, patients with systemic lupus erythematosus, and patients who developed hypertension after hemodialysis or renal transplantation. Data were collected by trained data management technicians after coding forms had been devised and pretested, and collated by electronic data processing. This review presents the available preliminary information concerning these 110 patients. Gaps in the coding and availability of information have been identified. Where quantitative information is incomplete, qualitative approaches have been substituted. Frequency distribution by diagnosis, age, and sex of 110 patients with renal hypertension is presented in Table 1. The nine diagnostic categories were derived from the data and from the experience of the attending nephrologist.
Symptoms Associated with Renal Hypertension Information concerning 28 specific presenting symptoms was coded in the registry. No symptom occurred in a frequency of 50 per cent or *Assistant Professor of Pediatrics, University of Southern California School of Medicine, Los Angeles, California
t Professor of PediatriCS, University of Southern California School of Medicine; Head, Division of Nephrology, Children's Hospital of Los Angeles, California Supported by the California Regional Medical Programs, Contract ROP-75G-513-0-147P (111174 to 6/30/76) Pediatric Clinics of North America-Vol. 23, No.4, November 1976
795
796
DAVID L. OLSON AND ELLIN LIEBERMAN
Table 1. Registry of 110 Patients with Renal Hypertension (1970 to 1975) SEX NO. OF
AGE RANGE
MEDIAN AGE
(Years)
(Years)
DIAGNOSIS
PATIENTS
Male
Female
Acquired renal parenchymal disease (hemolytic uremic syndrome, renal trauma, nephrotic syndrome, chronic pyelonephritis) Acute glomerulonephritis Congenital malformations Nonurologic (infantile polycystic disease, bilateral renal hypoplasia, solitary cyst) Urologic (vesicoureteral reflux, obstructive uropathy, neurogenic bladder, exstrophy of bladder) Progressive renal parenchymal disease" Nonurologic (membranoproliferative glomerulonephritis, focal glomerulosclerosis, chronic glomerulonephritis) Urologic (chronic nonobstructive pyelonephritis, obstructive uropathy) Renovascular hypertensiont End stage renal disease Other
34
12
22
.3-18
9.5
21
16
5
2-14
7.5
15
4
11
.1-17
1.0
5
4
1
.3-16.5
9
4
5
.2-17
7.0
5
4
.4-16.5
9.0
11
4
7
.3-11
5.0
4 4
.1-17.5 .5-17
5 5
13
9.0 13.5
*Increasing clinical and laboratory evidence of renal failure but no end-stage renal disease (GFR < 10 ml/min/1. 73 M2). tDefined as angiographically demonstrated main or segmental renal artery stenosis.
greaterin this series and only those symptoms which appeared in 10 to 30 per cent are included in Table 2. Data were further analyzed to exclude symptoms of 21 children with acute glomerulonephritis to determine if their data might have skewed the findings. The data listed for these seven symptoms, both for the entire group and for the remainder without acute glomerulonephritis, suggest that these symptoms are representative of both acute and chronic renal disorders in the pediatric age group and that symptoms usually ascribed to acute glomerulonephritis can be expected in other acute and chronic renal diseases. The expected frequency of well known symptoms associated with chronic and/or progressive renal failure, such as fatigue, lethargy, failure to thrive, or perceptible change in growth velocity, was not found in 19 patients with compromised renal function. This discrepancy may be explained by the fact that the data coded represent a compilation of the admitting histories and physical
797
RENAL HYPERTENSION IN CHILDREN
Table 2. Presenting Symptoms of Renal Hypertension in 110 Patients as Compared with Symptoms in 89 Patients Without Acute Nephritis WHOLE GROUP eN SYMPTOM
Swelling Headache Nausea/vomiting Fever Poor appetite Fatigue Dizziness
= 110)
WITHOUT NEPHRITIS eN
= 89)
No. of Patients
Per Cent
No. of Patients
Per cent
34 33 30 18 17 12 10
31 30 27 16 15 11 9
18 24 20 9 11 11 10
20 27 22 10 12 12 11
examinations by medical students, interns, residents, and attending physicians; it remains uncertain whether complaints suggestive of chronic renal failure did not exist in this sample or whether historical information relating to these symptoms was missing.
Physical Findings Seventeen variables, other than hypertension, relating to cardiovascular findings, fundoscopic abnormalities, organomegaly, edema, and bruit were sought as part ofthe coding for positive physical findings at the time of initial evaluation. Only those findings with a frequency greater than 10 per cent have been included. While heart murmur was listed in 42 of 110 patients (38 per cent), preliminary review of the data indicate that murmur was included without commentary as to its significance. Arteriolar narrowing was found on examination of the optic fundi in 15 per cent of the patients; retinal hemorrhage, exudates, and papilledema were not recorded. Peripheral edema, hepatomegaly, rales, and increased heart size, noted in from 10 to 25 per cent of the patients, might have been anticipated in a group of children with various types of renal hypertension. The listing of "hepatomegaly" did not require a description of measurement of liver size and the 20 patients with hepatomegaly include children with acute glomerulonephritis, hemolytic uremic syndrome, and infantile polycystic disease of the kidney. Data concerning typical physical findings of chronic renal failure were not included in the registry. Nevertheless, the signs which reflect diminished glomerular filtration rate and ultimately become reflected in Table 3. Physical Findings in 110 Patients with Renal Hypertension
Heart murmur Peripheral edema Hepatomegaly Retinal arteriolar narrowing Rales Increased heart size
NO. OF PATIENTS
PER CENT
42 28 20 17 11 11
38 25 18 15 10 10
798
DAVID L. OLSON AND ELLIN LIEBERMAN
the clinical syndrome of uremia should be sought in hypertensive children. These signs are protein calorie malnutrition, uremic odor, sallow complexion, osteodystrophy, pruritus, metastatic calcification, central nervous system disturbances, peripheral neuropathy, pericarditis or pneumonitis. Diagnosis The simplest way to approach the differential diagnosis of renal hypertension is to separate disorders associated with acute hypertension (often reversible) from those associated with chronic hypertension. Children with acute renal hypertension classically present with a history of prior good health followed by the abrupt emergence of signs and symptoms reflecting renal disease, for example, change in urinary habits, decreased urine output, or gross hematuria. Headache, nausea, and vomiting are common. Physical examination does not reveal evidence of longstanding severe or malignant hypertension such as facial palsy, hypertensive retinopathy (hemorrhages, exudates, papilledema) or cardiomegaly due to left ventricular hypertrophy. Rash, fever, or costovertebral angle tenderness may suggest more specific causes of acute disease. In contrast to chronic or end-stage renal failure, pallor, growth failure, osteodystrophy, and other signs of uremia are absent in patients with acute renal hypertension. Laboratory findings which may be useful in differentiating conditions associated with acute or chronic hypertension are summarized in Table 4. This table is idealized to convey patterns of laboratory findings, and it must be borne in mind that exceptions exist. The registry data did not permit analysis oflaboratory results, and these data will be presented in subsequent publications. The most common causes of hypertension secondary to acute renal disorders are acute glomerulonephritis, anaphylactoid purpura, and hemolytic uremic syndrome. Chronic hypertension may result from renovascular or renal parenchymal disease. One special group of patients with renal parenchymal disease is that with asymmetric disease, i.e., a unilateral small kidney. These two groups (renovascular and asymmetric renal parenchymal) are Table 4. Laboratory Studies in Patients with Renal Hypertension CHRONIC
Urinalysis HemoglobinJhematocrit Blood chemistries BUN/creatinine Calcium Phosphorus Alkaline phosphatase Other studies Electrocardiogram Chest x-ray: heart size X-ray: osteodystrophy
ACUTE
Parenchymal
+
+
Normal
t
Normalor Normal or Normal
t t
Normal or LvH Normal or t
Renovascular
t
Normal
t t t t
Not always normal Normal Normal Normal
Normal or LVH Normal or t
+
LvH
t
RENAL HYPERTENSION IN CHILDREN
799
important because hypertension in affected children may be cured by surgery. Because these conditions are relatively rare and many special investigative studies have been developed only during the past decade, descriptions of clinical and laboratory findings in such pediatric patients are not available. Some information, however, has been collected from a retrospective-prospective survey of a group of patients with renovascular or renal parenchymal hypertension at CHLA. These data are not completely integrated into the registry and therefore cannot be presented in tabular form. . These patients presented with moderate to severe hypertension from infancy through childhood. Both sexes were equally affected. The children with renovascular disease (unilateral or bilateral major renal artery or segmental renal artery stenosis) all had normal urinalyses and renal function studies; those with asymmetric renal parenchymal disease were more likely to have abnormal urinalyses and slight elevations in determinations of BUN or serum creatinine. Intravenous pyelography or renal scintigraphy and renograms identified those patients with hypertension secondary to unilateral renal parenchymal disease. Rapid sequence intravenous pyelogram, renal scintigraphy, renogram, and measurement of peripheral renin activity have been used extensively in hypertensive adults to identify those with renovascular disease. 1. 4. 5 Findings on RIVP which indicate that renal artery stenosis may be present in adults include a discrepancy in size of 1.5 cm or greater between the two kidneys, differences in the appearance, concentration, and excretion of contrast, and the presence of ureteral notching (implying the existence of arterial collateral circulation). Positive findings on renal scintigraphy and on renograms using 131I-hippurate which suggest major renal artery stenosis include a disparity of greater than 10 per cent of isotopic counts between the two kidneys and significant differences in the curves on the renogram which reflect the vascular phase, concentration, and excretion of the isotope by the two kidneys. Peripheral renin activity is elevated in the majority of adults with renovascular hypertension. 8, 9 Renal angiography, however, remains the definitive diagnostic test. Comparative data for children have not been published. Measurement of renin activity in the renal veins has been used to identify patients with unilateral renal disease causing hypertension and to predict surgical curability.7-9 If the renal vein renin ratio exceeds 1.5, indicating that the diseased kidney is secreting at least 50 per cent more renin than the contralateral kidney, a revascularization procedure or unilateral nephrectomy has been associated with cure of hypertension in approximately 80 per cent of adults with unilateral renal disease. 8 Data to evaluate the usefulness of this test in children with renal hypertension are inadequate. In the group of children with renovascular hypertension at CHLA the following results were found: rapid sequence intravenous pyelogram was suggestive of renovascular disease in less than 50 per cent, increased plasma renin activity was found in the majority of children, and renal scintigraphy and renograms using 131I-hippurate were positively correlated with the results of renal angiography in 64 per cent. The renal vein renin ratio exceeded 1. 5 in 6 patients and 3 of these patients underwent surgery with cure of hypertension in 2 of the 3. These data suggest that
800
DAVID L. OLSON AND ELLIN LIEBERMAN
measurement of plasma renin activity, renal scintigraphy and renograms, and rapid sequence intravenous pyelograms are useful screening tests, but definitive diagnosis rests with renal angiography. More experience must be accumulated to assess the utility of renal vein renin ratios in predicting surgical curability of renovascular hypertension in children. Intravenous pyelography and renal scintigraphy identified all patients at CHLA with hypertension caused by asymmetric renal parenchymal disease, and plasma renin activity was elevated in every patient in whom it was measured. Unilateral nephrectomy was done in two patients after the renal vein renin ratio was found to exceed 1.5. This procedure resulted in cure of hypertension in one patient with an angiographically normal contralateral kidney and resulted in failure in the second patient with an angiographically abnormal contralateral kidney.
Chronic Renal Parenchymal Hypertension The suspicion that a child may have progressive renal insufficiency, chronic renal insufficiency, or end-stage renal disease evolves readily from a review of the history, physical examination, and analysis of unsophisticated laboratory results. These children characteristically have often been regarded as sickly throughout their lives or from some indeterminate time, do not grow well, and are usually unable to keep pace with their peers physically, emotionally, or intellectually. Physical findings may range from a few signs-i.e., pallor, poor growth, presence or absence of renal masses-to the full blown picture of uremia. Laboratory confirmation of renal functional impairment confirms the diagnosis of chronic renal disease. Following this analysis, the most important questions are: Is any abnormal component of the child's clinical status reversible? Is there a specific diagnosis for which specific therapy is indicated? What is optimal comprehensive therapy?
Treatment Conditions which may be cured by surgical intervention include major or segmental renal artery stenosis, potentially curable by revascularization procedures and unilateral renal parenchymal diseases such as renal hypoplasia, chronic pyelonephritis, unilateral renal trauma, and unilateral ureteral obstruction, potentially curable by nephrectomy or relief of obstruction. If hypertension is not of long duration and the contralateral kidney is not irreversibly damaged by hypertension per se, surgical procedures on the affected kidney may result in permanent cure, defined as normal blood pressure for sex and age without medication in a child who has normal renal function which can support growth until physical maturity is achieved. Surgical failure may be due to technical errors, inappropriate selection criteria, inadequate evaluation of renal function and of the contralateral kidney, lack of lateralization of renal vein renin ratios (i.e., < 1.5), and incorrect diagnosis. A program of medical therapy must then be developed. The development of a medical treatment plan must take into account the duration and severity of hypertension. Ajudgment must be reached as to whether hypertension is acute and therefore likely to respond to relatively low doses of mild antihypertensive agents, or chronic and likely to be more resistant. Knowledge of the specific disease and insight into the
RENAL HYPERTENSION IN CHILDREN
801
pathogenesis of hypertension permit the physician to develop a rationale for the use of diuretics, vasodilators, inhibitors of renin secretion, or drugs which act by their influence upon the sympathetic nervous system. For example, evidence accumulated from studies of body composition in experimental animals and adults suggests that hypertension associated with renal parenchymal disease is attended by expansion of extracellular fluid volume and/or plasma volume;lO diuretic therapy in this situation would seem to be the most logical first step. Other factors related to the pathogenesis of renal hypertension include the renin-angiotensin system and its relationship to the autonomic nervous system (especially through the sympathetic innervation of the juxtaglomerular apparatus which influences renin release) and circulating levels of plasma catecholamines which are potent vasoconstrictors. These and other factors have not been investigated in children with various types of renal hypertension. Another important consideration in the choice, route, and dosage of antihypertensive drugs is an assessment of renal function. Is the serum creatinine elevated solely because of reduced glomerular filtration due to glomerular inflammatory changes, necrosis, and scarring of glomerular structures and fibrin deposition? Or does the creatinine elevation reflect arteriolar constriction leading to hypertension and reduction of glomerular filtration rate? Or, are the two phenomena combined so that it is not possible to determine the relative contribution of each? The majority of diuretic and antihypertensive agents have been available long enough to accumulate data and experience. However, because of the complexity of designing clinical protocols and the restraints imposed concerning the use of these agents in children, very little information has been published concerning their effectiveness (except in short-term trials) in conditions other than acute glomerulonephritis. Studies concerning the short-term effectiveness of furosemide 6 and diazoxide 3 in acute nephritis are available and an article on sodium nitroprusside has been published recently.2 Accordingly, the recommendations presented below are based on experience at CHLA and have not been subjected to critical analysis. An empirical schema for a stepwise approach to treatment of hypertension is presented in Figure 1 and reflects both the current practice at CHLA and general recommendations for adults with essential and renal hypertension. Therapy is usually initiated (except in hypertensive emergencies) with a thiazide diuretic. If diuretic therapy does not provide adequate blood pressure control, hydralazine or methyldopa is added (Fig. 1, Step II). The dose of either agent is increased until blood pressure control is achieved or until significant side effects occur. Relatively common side effects of hydralazine include headache, nausea, and vomiting, and common side effects of methyldopa are lethargy and decreased mentation. These side effects often disappear a few days after initiation of therapy or after increasing the dose, but persistence may necessitate decreasing the dose or stopping the drug altogether. Rare side effects of methyldopa include hemolytic anemia and hepatocellular disease, and a rare complication of hydralazine therapy is a lupus-like syndrome with or without a positive antinuclear antibody test. At CHLA a positive antinuclear antibody test has been encountered rarely and only when large doses of hydralazine (Le., 200 mg daily in adolescents) have been used for long
802
DAVID
L.
OLSON AND ELLIN LIEBERMAN
HYPERTENSION
I
I Medical I Dietary Therapy Sodium Calories
Surgical
~Cure
Noncure
Pharmacologic Therapy }
Mild Hypertension
)
Mild to Moderate Hypertension
STEP I
Diuretics
~
HYdralaWYldopa
Triple Therapy
)
Moderate and/or Resi slant Hypertension
STEP 11
STEP III
Guanethidine
Chronic Hypertension r - - - - - - or - - - - - - - ,
Diozoxide or Furosemide
Nitroprusside
Hypertensive Emergency
STEP IV
Figure 1. An empirical schema for treatment of renal hypertension is depicted.
periods (over 3 months). Hydralazine-induced lupus syndrome has not developed in any child or adolescent during the past 10 years at CHLA. If a combination of two agents is ineffective in achieving blood pressure control, combined therapy with a thiazide diuretic, methyldopa, and hydralazine is recommended (Fig. 1, Step III). A more potent diuretic, such as furosemide, may be substituted for the thiazide. Iftriple therapy is required, however, it constitutes a signal that one or more ofthe following factors should be assessed: (1) Is the patient taking the medication? (2) Is the present medication prescribed in dosages and at times which provide maximal therapeutic effectiveness? (3) Has a superimposed event which may exacerbate hypertension (such as acute hydronephrosis or an emotional crisis) taken place? (4) Has the patient inadvertently received agents with pressor effects, such as corticosteroids, sympathomimetics, or oral contraceptives with estrogens? (5) Is the patient ingesting excessive amounts of sodium in the form ofN aCI or food preservatives? Once it is ascertained that the above factors are not creating "resistant" hypertension, then triple therapy may be used. As an alternative to therapy with these three agents for moderate to severe hypertension, guanethidine may be used. The experience with guanethidine is limited in pediatrics and it may cause orthostatic hypotension. Guanethidine should be reserved for patients who are unresponsive to more conservative therapy.
RENAL HYPERTENSION IN CHILDREN
803
Intravenous diazoxide is used for treatment of hypertensive emergencies (Fig. 1, Step IV), defined as blood pressure of 200 mm Hg systolic, 140 diastolic, or greater (regardless of age), usually in a patient with chronic hypertension (except in the setting of dialysis or renal transplantation) and with evidence of target organ involvement (i.e., hypertensive retinopathy, seizures, facial palsy, cardiomegaly or congestive heart failure). Diazoxide is given by rapid bolus intravenous injection, avoiding extravasation with subsequent necrosis of surrounding tissues. An antihypertensive effect may be expected within minutes and no later than one hour if the drug has been administered correctly; a repeat dose should not be given until 60 minutes have elapsed because of the possibility of causing hypotension. Because diazoxide is such a potent vasodilator, it is a powerful antihypertensive agent and is usually not needed for the treatment of hypertension in acute renal disorders such as acute glomerulonephritis. Intravenous furosemide (1 to 2 mg/kg) is needed to counteract the salt and water retaining properties of diazoxide. After control of severe hypertension has been achieved with diazoxide, agents such as methyldopa, hydralazine, and diuretics may be instituted to maintain blood pressure control. The experience with sodium nitroprusside in hypertensive emergencies is very limited in pediatrics. At CHLA this agent has been used in the rare instance when diazoxide has failed to control hypertension and in one instance when repeated administration of diazoxide led to severe hyperglycemia and elevation of the serum amylase. Sodium nitroprusside is given by continuous intravenous infusion starting with a dose of 0.5 mcg/kg/minute and increasing to a maximum of 5 mcg/kg/minute. Its onset of action is immediate and the dose must be titrated with the physician in attendance. Side effects include thiocyanate toxicity (nitroprusside is metabolized to thiocyanate) and hypothyroidism. In small children nitroprusside has rarely been used, and its use must be limited to only a few days. Outcome Outcome of treatment in 100 of 110 registry patients with renal hypertension is presented in Table 5. Ten patients, those with end-stage renal disease and those with miscellaneous conditions, were excluded from this analysis. These categories included patients with the most severe hypertension and with progressive decrease in renal function; adequate blood pressure control was most difficult to achieve in these patients who constitute a critical group because the majority will eventually enter dialysis and transplant programs in which the patient's course may be complicated by severe hypertension and target organ damage. Three of 11 patients with renovascular hypertension underwent surgical correction with subsequent cure. Seven of these are on medical therapy and remain mildly hypertensive. Patients with abnormal blood pressure values without therapy have mild hypertension which is considered not sufficiently elevated to treat or is resolving. Summary Preliminary results of this retrospective-prospective analysis of renal hypertension in 110 children indicate that hypertension may be secondary
804
DAVID
L.
OLSON AND ELLIN LIEBERMAN
Table 5. Outcome in 100 Patients with Renal Hypertension
Acquired renal parenchymal disease Acute glomerulonephritis Congenital malformations (urologic/nonurologic) Renovascular hypertension Progressive renal parenchymal disease (urologic/nonurologic) TOTAL
ABNORMAL BLOOD
PRESSURE
PRESSURE
Without Therapy
With Therapy
Without Therapy
With Therapy
Expired
34
14
7
2
11
0
21
13
20
4
3
5
2
11
3
0
7
0
14 100
4 38
11
7 31
0 3
NO. OF DIAGNOSIS
NORMAL BLOOD
PATIENTS
5
6
2 17
to a wide variety of acute, progressive, and chronic renal diseases which may be either congenital or acquired. Affected children may be detected at any time from infancy through adolescence. Symptoms usually associated with acute glomerulonephritis (Le., headache, swelling, nausea, vomiting, anorexia, fatigue, dizziness, and fever) occur in both acute and chronic renal diseases associated with hypertension. Headache and swelling are the most common symptoms in this series. Peripheral edema, rales, and increased heart size were found in between 10 and 25 per cent of these children. Differential diagnosis may be approached by a consideration of causes of acute and chronic hypertension. The child with chronic renal disease usually presents with a long history of fatigability, poor growth, and pallor, and laboratory tests reveal elevation of the creatinine and B UN along with anemia, hypocalcemia, and hyperphosphatemia. In contrast, the child with acute renal disease and hypertension presents with a history of prior good health followed by the abrupt onset of signs and symptoms of renal disease; laboratory tests usually reveal modest elevations of creatinine and BUN, anemia is unusual, an abnormal urinalysis is common, and serum calcium and phosphorus levels are usually normal. Renovascular and asymmetric renal parenchymal disease represent uncommon but important conditions because surgery may be curative. Treatment may be surgical, medical, or combined. Surgical conditions include renal trauma, hydronephrosis, asymmetric renal disease, and renal arterial disease. Adequate blood pressure control without medication can be expected following surgery in instances of unilateral involvement with a normal contralateral kidney. Meticulous assessment of the contralateral kidney is needed to determine that it is normal. If surgery is unsuccessful or is not indicated, pharmacologic therapy is
RENAL HYPERTENSION IN CHILDREN
805
initiated with a stepwise regimen starting with the mildest agent (e.g., thiazides) and then adding additional antihypertensive drugs when adequate blood pressure control has not yet been achieved. The goal of therapy is the lowest, safest, tolerated blood pressure levels. Long-term, carefully designed studies of antihypertensive agents for children with renal hypertension are not available. The need for collection and critical analysis of data concerning the clinical course of children with renal hypertension is evident from a review of the literature and from the preliminary data presented in this series. The presentation of such information and a critique of outcome variables will provide a basis for program planning for affected children and improvement in patient care where indicated.
REFERENCES 1. Bookstein, J. J., Abrams, H. L., Buenger, R. E., et al.: Radiologic aspects of renovascular
2. 3. 4. 5. 6. 7. 8. 9. 10.
hypertension. Part 2. The role of urography in unilateral renovascular disease. J.A.M.A., 220:1225, 1972. Gordillo-Paniagua, G., Velasquez-Jones, L., Martini, R., et aI.: Sodium nitroprusside treatment of severe arterial hypertension in children. J. Pediat., 87:799,1975. Kohaut, E. C., Wilson, C. J., and Hill, L. L.: Intravenous diazoxide in acute poststreptococcal glomerulonephritis. J. Pediat., 87:795, 1975. Maxwell, M. H., Lupu, A. N., and Taplin, G. V.: Radioisotope renogram in renal arterial hypertension. J. UroI., 100:376,1968. Quinones, J. D., Varma, V., and Macal, 0.: Radionuclide and pyelographic tests in screening for renovascular hypertension. Arch. Intern. Med., 129:570, 1972. Repetto, H. A., Lewy, J. E., Brando, J. L., et al.: The renal functional response to furosemide in children with acute glomerulonephritis. J. Pediat., 80:660, 1972. Schambelan. M., Glickman, M., Stockigt, J. R., et al.: Selective renal-vein renin sampling in hypertensive patients with segmented renal lesions. New Engl. J. Med., 290:1153, 1974. Stockigt, J. R., Noakes, C. A., CollinS, R. D., et al.: Renal vein renin in various forms of renal hypertension. Lancet, 1 :1194, 1972. Vaughan, E. D., Buhler, F. R., Laragh, J. H., et al.: Renovascular hypertension: Renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow and score for surgical curability. Am. J. Med., 55:402, 1973. Vaughan, E. D., Buhler, F. R., Laragh, J. H., et al.: Hypertension and unilateral parenchymal renal disease. Evidence for abnormal vasoconstriction-volume interaction. J.A.M.A., 233:1177,1975.
Division of Nephrology Childrens Hospital of Los Angeles Box 54700, Terminal Annex Los Angeles, California 90054