Transcript No Slide Title

Allopurinol for the
treatment of essential
hypertension (EHTN)
Farahnak Assadi, MD
Emeritus Professor of
Pediatrics
Chief Section of Nephrology
Why Do Some People Develop EHTN?
?
Obese/HTN (20-40%)
Normal Weight/BP (60-80%)
Obese/HTN: Overeat and exercise less BUT WHY?
Why Do Some Kids Develop EHTN?
?
Obese/HTN (10-20%)
Normal Weight/BP(80-90%)
Obese/HTN: Overeat and exercise less BUT WHY?
Developmental Basis of Obesity HTN
A bad start
that lasts
a lifetime!
Data indicating that obesity HTN has its origins during development and
environmental chemicals exposures play a major role
When Do Diseases Actually Start, and
What Causes Diseases?
Disease
Time ?
Genetics
Environment
Both Genetics and Environment Factors
Control Our Life
Environmental
factors
Epigenetic
(stable but plastic) (chemicals, diet, drugs,
stress, behavior)
Inter-individual variability
Susceptibility to Disease, Toxicants,
Drugs, Altered behavior
Genetic
polymorphisms
(born with)
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
The role of kidney in SHR
Rettig R. J Human Hypertens 1993:7:177-180
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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
Blaustein MP. Hypertension 1984;6:445-453
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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.
Ayman D. Arch Intern Med 1934;53:792-802
©2007 RUSH University Medical Center
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
Change in LV mass index
(%)
0
Diuretics
blockers
Calcium
channel
blockers
ACE
inhibitors
-5
-10
7%
6%
9%
13%
-15
p<.01
-20
p<.01
-25
Schmieder RE et al. JAMA. 2006
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.
Patient population (pretreatment)
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
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.
Results
Mono therapy (GI)
Combined therapy (G II)
(n=20)
(n=24)
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
Parameter
P value
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
Hypertension (HTN): A Significant CV and
Renal Disease Risk Factor
CAD
CHF
LVH
Stroke
Hypertension

Morbidity
CKD
Peripheral
vascular disease
National High Blood Pressure Education Program Working Group, 2012

Disability
Prevalence of CVD
• Estimated Number of Persons With CVD in the US
10
Prevalence (millions)
20
30
40
12,200,000
CHF
4,600,000
Stroke
4,400,000
Other
60
50,000,000
High BP
CAD
50
2,800,000
BP=blood pressure, CAD=coronary artery disease, CHF=congestive heart failure
American Heart Association® . 2000 Heart and Stroke Statistical Update. 2009
(24%)
The Metabolic Syndrome*
Risk Factor
Abdominal obesity†
(Waist circumference‡)
Men
Women
TG
HDL-C
Men
Women
Blood pressure
Fasting glucose
Defining Level
>102 cm (>40 in)
>88 cm (>35 in)
150 mg/dL
<40 mg/dL
<50 mg/dL
130/85 mm Hg
110 mg/dL
*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.
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
Weight reduction
Approximate SBP reduction
(range)
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
Lifestyle Modifications
Not at Goal Blood Pressure >95 percentile
(in adolescents>125/75 mmHg even if less the 90 percentile)
Initial Drug Choices
Without Compelling
Indications
Stage 1 Hypertension
With Compelling
Indications
Stage 2 Hypertension
Between 95th and 99th percentile plus 5
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
(>95th
percentile + 5 mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
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
The 4th Task Force Report on High BP in Children and
Adolescents Pediatrics 2004; 114:555-574
*Average SBP and DBP, on >3 occasions
**Average SBP or DBP, on >3 occasions
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
Essential
GN
C3, ANA, ANCA
UPJ,VUR
Diuretic scan, VCUG
RVH, Hyperaldostronim
DTPA scan, PRA/Aldo, MRA
Potential Pathogenic Properties
of Angiotensin II
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
©2007 RUSH University Medical Center