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Allopurinol for the treatment of essential hypertension (EHTN)
Farahnak Assadi, MDEmeritus Professor of PediatricsChief Section of Nephrology
Why Do Some People Develop EHTN?
Normal Weight/BP (60-80%)Obese/HTN (20-40%)
??
Obese/HTN: Overeat and exercise less BUT WHY?
Why Do Some Kids Develop EHTN?
Normal Weight/BP(80-90%)Obese/HTN (10-20%)
??
Obese/HTN: Overeat and exercise less BUT WHY?
Developmental Basis of Obesity HTN
Data indicating that obesity HTN has its origins during development and environmental chemicals exposures play a major role
A bad startthat lastsa lifetime!
When Do Diseases Actually Start, and What Causes Diseases?
Epigenetic(stable but plastic)
Genetic polymorphisms
(born with)
Inter-individual variability
Environmental factors
Susceptibility to Disease, Toxicants, Drugs, Altered behavior
(chemicals, diet, drugs, stress, behavior)
Both Genetics and Environment Factors Control Our Life
Epigenetic Causes of Overeating and Lack of Exercise?
• Drug use (steroids, antidepressants, other meds?)
• Exposure to viruses (adenovirus 36)
• Environment– Stress (increased glucocorticoids)
– Nutrition (dietary salt)
– Lack of sleep
– Environmental chemicals
Epidemiologic studies
• In Japanese the incidence of ETN approaches 50%• The mean sodium intake in Japanese is >400
mmol/day.• In Eskimo the average sodium intake is very low
<50 mmol/day and EHTN is virtually nonexistent.
©2007 RUSH University Medical Center
Renal Handling of Sodium
• Excessive sodium intake alone is not sufficient to cause HTN, because the sodium retention and ECF volume expansion result in increased urinary sodium excretion that eventually normalize cardiac output and BP.
• Additional predisposing factors must exist that lead to the development of HTN in certain individual when the sodium intake is >60-70 mmol/day.
• Guyton AC. Hypertension 1987;10:1-6
©2007 RUSH University Medical Center
©2007 RUSH University Medical Center
The role of kidney in SHR
Rettig R. J Human Hypertens 1993:7:177-180
Role of kidney in Human EHTN
• In patients with ESRD due to EHTN, bilateral nephrectomy and a well-functioning allograft from a normotensive cadaver, cures EHTN
• Incidence of EHTN in recipients of cadaver kidneys correlates with the incidence of EHTN in the family of donors
• Curttis jj et al. N Engl J Med 1983;309:1009=1015• Guidi E, et al. Nephron 1985;41:14-21
©2007 RUSH University Medical Center
Genes Causing EHTN
• Aldosterone synthesis gene (CYp11B2) mutations.
• Angiotensin II type 1 receptor gene (ATI) polymorphism.
• Endothelial nitric oxide synthesis gene (eNOS) mutations.
• G-protein β3 subunit gene (GNβ3) variant. • Caulfield M et al N Engl J Med 1994;330:1629-1633
• Benjafield AV et al. Hypertens.1998;32:1094-1097
• Siffert W, et al. Nat Genetics 1998;18:45-48
• Davies E, et al. Hypertens. 1999;33:703-707
Impaired natriuresis: a prerequisite in EHTN• Increase ECF volume• Na/K ATPase inhibition• Increase ICF sodium concentration• Increase ICF calcium concentration• Vasoconstriction• Increase systemic vascular resistance• Development of EHTN
©2007 RUSH University Medical Center
Blaustein MP. Hypertension 1984;6:445-453
Pathogenesis of EHTN
• There is a genetically predetermined impairment in the renal ability to excrete sodium or “impaired natriuretic capacity.”
• The prevalence of EHTN among offspring has been reported to be 46% if both parents are hypertensive, and 28% if one parent is hypertensive, and only 3% if neither parent is hypertensive.
©2007 RUSH University Medical Center
Ayman D. Arch Intern Med 1934;53:792-802
Essential hypertension(EHTN)
• EHTN is a public Health problem worldwide and its burden on our health care system is becoming enormous.
• Many children with obesity are not aware that they have HTN.
• Over activity of renin-angiotensin system (RAS) is the main cause of primary HTN.
• RAS over activity can lead to myocardial hypertrophy, CVD and CKD and stoke.
©2007 RUSH University Medical Center
Douglas JG et al. Arch Intern Med 2003;163:525-541
Reversal of LV Hypertrophy By Antihypertensive Treatment
Schmieder RE et al. JAMA. 2006
Ch
ang
e in
LV
mas
s in
dex
(%)
0
-5
-10
-15
-20
-25
Diuretics blockers
Calciumchannelblockers
ACE inhibitors
p<.01
p<.01
7%6%
9%
13%
Uric acid and EHTN
• EHTN is frequently associated with hyperuricemia in both adult and pediatric patients.
• More than 60% of children with EHTN have serum uric acid (UA) levels above 5.5 mg/dL.
• UA causes HTN through the activation of the RAS, down regulation of nitric oxide, and vascular endothelial dysfunction.
• Elevated UA level is a predictor of incident HTN and cardiovascular disease.
• Feig DI et al. JAMA 2008;300:924-932
Hypothesis
• Treating EHTN with usual antihypertensive agents does not completely reduce cardiovascular risk related to uric acid (UA) levels.
• Lowering serum UA levels with allopurinol may provide greater benefit than simply treating HTN with the conventional therapy.
Purpose of the study
• ACE inhibition in combination with allopurinol may reduce BP more effectively than ACE inhibitor alone in hyperuricemic children with newly diagnosed EHTN.
Patients
• Forty- four children, aged 7-19 years, with newly diagnosed, never treated EHTN and serum UA levels > 5.5 mg/dL were studied.
• Patients were randomized in to two groups. Group 1 (n=20) received enalepril (0.3 mg/kg twice daily) for 8 weeks.
• Group 2 (n=24) received enalepril in combination with allopurinol (100 mg twice daily) for 8 weeks.
Exclusion criteria
• Patients excluded if they had pre-HTN, stage 2 HTN, white-coat HTN or known renal, endocrine, gastrointestinal tract, hepatic or CVD.
• Also excluded were patients with a fasting blood sugar greater than 110 mg/dL,hemoglobin A1C greater that 6%, CVD, had treated with medications known to cause high BP or increase serum UA level.
Characteristic Enalepril therapy (n=20)
Combined therapy
(n=24)
P value
Gender (N) Male (23)
Female (19)
Male (27)
Female (15)
NS
NS
Age, mean (year) 14.2 15.9 NS
BMI (%) 87 (86-89) 86 (85-90) NS
Systolic BP
(mmHg)
133 (129-136) 134 (128-137) NS
Diastolic BP (mmHg)
85 (82-86) 86 (80-97) NS
Serum UA
(mg/dL)
6.6 (5.9-7.4) 6.8 (6.1-7.6) NS
FEUA (%) 10.8 (8.1-12.3) 12.1 (8.7-12.4) NS
Patient population (pretreatment)
Methods
• Random urine samples were collected for routine urinalysis and determinations of sodium and uric acid levels.
• Blood samples were drawn for electrolytes, creatinine and uric acid concentrations.
• Fractional excretion of uric acid were calculated using the standard formula.
Parameter Mono therapy (GI)
(n=20)
Combined therapy (G II) (n=24)
P value
Change in systolic BP (mmHg)
-4.3 (-2.1 to -6.7) -8.2 (-7.2 to -9.8) 0.001
Change in diastolic BP
-2.4 (-1.1 to -2.2) -6.3 (-1.9 to -7.8) 0.006
Serum uric acid (mg/dL)
-5.1 (-5.8 to-6.7) -3.3 (-2.9 to-5.2) 0.002
FEUA
(%)
-3.3 (-3.4 to-4.1) -5.4 (-4.4 to-8.0) 0.004
Results
Conclusions
• Allopurinol in combination with enalepril can reduce BP more effectively than enalepril alone in hyperuricemic children with newly diagnosed EHTN.
• Strategies to lower the risk of CVD in children with EHTN should include monitoring serum uric acid level treatment regimens that lower uric acid may be indicated to decrease the incidence of CVD by reducing serum uric acid level.
Future Direction
• Increased dietary intake of fructose, which is a known cause of hyperuricemia, may be contributing to the current epidemic of obesity and HTN.
• Ongoing clinical trials will elucidate the role of uric acid in human HTN and will determine whether control of uuric acid may be a new way to prevent or treat EHTN.
The End….but just the beginning
©2007 RUSH University Medical Center
Peripheral vascular disease
Morbidity
Disability
CKD
CADCHFLVHStroke
Hypertension
National High Blood Pressure Education Program Working Group, 2012
Hypertension (HTN): A Significant CV and Renal Disease Risk Factor
Prevalence of CVD
10 20 30 40 50 60
High BP
CAD
CHF
Stroke
Other
50,000,000
12,200,000
4,600,000
4,400,000
2,800,000
Prevalence (millions)
BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure
• Estimated Number of Persons With CVD in the US
(24%)
American Heart Association® . 2000 Heart and Stroke Statistical Update. 2009
The Metabolic Syndrome*
*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.
<40 mg/dL<50 mg/dL
MenWomen
>102 cm (>40 in)>88 cm (>35 in)
MenWomen
110 mg/dLFasting glucose130/85 mm HgBlood pressure
HDL-C150 mg/dLTG
Abdominal obesity† (Waist circumference‡)
Defining LevelRisk Factor
Dietary Approaches to Stop Hypertension (DASH)
• Diet high in fruits and vegetables and low-fat dairy products lowers blood pressure (11 mmHg SBP/ 5 mmHg DBP lower than traditional US diet), including more than a sodium-restricted diet
• Recommends 7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy products, 2 or less meat, poultry, and fish
NEJM 1997; 366: 1117-24
Lifestyle Modification
Modification Approximate SBP reduction(range)
Weight reduction 5–20 mmHg/10 kg weight loss
Adopt DASH eating plan
8–14 mmHg
Dietary sodium reduction 2–8 mmHg
Physical activity 4–9 mmHg
Moderation of alcohol consumption
2–4 mmHg
Indications for Antihypertensive Drug Therapy in Children
with Stage 1 HTN
• Persistent HTN despite non-pharmacologic measures
• Symptomatic HTN• Secondary HTN• Hypertensive target-organ damage• Diabetes (types 1 and 2), CKD, obesity
Evaluation: The Four Questions
• What is the cause of my hypertension?
– Primary hypertension most prevalent but secondary causes more common than in adults
– The younger the child and the more severe the hypertension; the more likely to be a secondary etiology
• What do we do about all this?
Algorithm for Treatment of EHTN
Not at Goal Blood Pressure >95 percentile (in adolescents>125/75 mmHg even if less the 90 percentile)
Initial Drug Choices
Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)
as needed.
With Compelling Indications
Lifestyle Modifications
Stage 2 Hypertension (>95th percentile + 5 mmHg) 2-drug combination for most
(usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)
Stage 1 Hypertension
Between 95th and 99th percentile plus 5 Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB, or combination.
Without Compelling Indications
Not at Goal Blood Pressure
Optimize dosages or add additional drugs until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Evaluation: The Four Questions
• Am I really hypertensive?Repetitive measurements/ABPM
• What risk factors for CVD do I have?Prmaturity, low birth weight, family history of
diabetes, hypercholesterolemia, CKD • What has HTN done to my body?
Look for end organ damage• CVD, CKD or stroke; • Evaluation of subtle subclinical changes
(microalbuminuria, non-dipper)
Defining Pediatric HTN in children
Normal blood pressure BP <90th percentile
Pre-hypertension BP between 90th and 95th percentile, or if BP >125/75 mmHg even if < 90th percentile
Stage 1 hypertension BP between 95th and 99th percentile plus 5 mmHg
Stage 2 hypertension BP > 99th percentile + 5 mmHg
*Average SBP and DBP, on >3 occasions **Average SBP or DBP, on >3 occasions
The 4th Task Force Report on High BP in Children and Adolescents Pediatrics 2004; 114:555-574
Causes of pediatric HTN
• Primary HTN is most prevalent• Secondary causes is more common than in
adults• The younger the child and the more severe
the HTN; the more likely to be a secondary etiology
©2007 RUSH University Medical Center
Practical approach to diagnosis of HTN
Obtain UA, BMP, lipid profile, renal sonogram, ECHO
Normal Abnormal UA Abnormal sonogram Metabolic alkalosis
C3, ANA, ANCA Diuretic scan, VCUG DTPA scan, PRA/Aldo, MRA
Essential GN UPJ,VUR RVH, Hyperaldostronim
©2007 RUSH University Medical Center
Kidneys
Increased intraglomerular pressure
Increased protein leak
Glomerular growth and fibrosis
Increased sodium reabsorption
Decreased renal blood flow
Adapted from Opie and Gersh. Drugs for the Heart, 2001
Potential Pathogenic Propertiesof Angiotensin II