Pediatric Hypertension Nephrologist View

Pediatric Hypertension Pediatric Hypertension A Nephrologists ViewA Nephrologists View

Jeremy Gitomer, MDJeremy Gitomer, MD

Pediatric NephrologyPediatric Nephrology

Alaska Kidney ConsultantsAlaska Kidney Consultants

Goal of LectureGoal of Lecture

Scary thought!Scary thought!

Think of pediatric hypertension as a Think of pediatric hypertension as a nephrologist doesnephrologist does

DefinitionDefinition

Pediatric hypertension is defined as a blood Pediatric hypertension is defined as a blood pressure greater than the 95pressure greater than the 95 thth percentile blood percentile blood pressure for age, sex and length for patients pressure for age, sex and length for patients without comorbidities. without comorbidities.

Patients with comorbidities are defined as Patients with comorbidities are defined as hypertensive when the blood pressure is greater hypertensive when the blood pressure is greater than the 90%.than the 90%.

ComorbiditiesComorbidities Diabetes, Renal disease, Cardiac disease, Obesity, Diabetes, Renal disease, Cardiac disease, Obesity,

Family historyFamily history

Who Cares?Who Cares?

Cardiovascular disease is the number one Cardiovascular disease is the number one cause of death in the United States.cause of death in the United States.

Hypertension poses a significant risk for Hypertension poses a significant risk for the development of cardiovascular related the development of cardiovascular related mortality or morbidity.mortality or morbidity.

ArteriosclerosisArteriosclerosis

Cause for ConcernCause for Concern

Metabolic syndrome is increasing at an Metabolic syndrome is increasing at an alarming rate.alarming rate. Insulin resistanceInsulin resistanceObesityObesityHypertensionHypertension

Obesity is rampantObesity is rampantHypertension prevalence is increasing Hypertension prevalence is increasing

rapidlyrapidly

Cause for ConcernCause for Concern

Improvements in Improvements in neonatal survival will neonatal survival will impact the incidence impact the incidence of hypertensionof hypertension

N Engl J Med 2003; 348:101-108, Jan 9, 2003.

Preventive MedicinePreventive Medicine

Treatment of pediatric hypertension is Treatment of pediatric hypertension is actually preventive medicine.actually preventive medicine.

Patients don’t die of heart attacks or Patients don’t die of heart attacks or strokes in their pediatric years. strokes in their pediatric years.

Likely will have cardiovascular events at a Likely will have cardiovascular events at a younger age than expected.younger age than expected.

Diagnosis of HypertensionDiagnosis of Hypertension

3 office blood pressure readings greater 3 office blood pressure readings greater than the upper limit of normalthan the upper limit of normal

20 mm Hg higher than the limit on any one 20 mm Hg higher than the limit on any one reading is considered diagnostic of reading is considered diagnostic of hypertensionhypertension

White Coat HypertensionWhite Coat Hypertension

Defined as a normal blood pressure at Defined as a normal blood pressure at home but elevated in the office.home but elevated in the office. Increased sympathetic toneIncreased sympathetic toneNo evidence of increased cardiovascular No evidence of increased cardiovascular

mortalitymortality

Problem with Office BP Problem with Office BP MeasurementsMeasurements

Ziac Drug StudyZiac Drug StudyPatients enrolled diagnosed with Patients enrolled diagnosed with

hypertensionhypertensionRepeat screening SBP at visit 1 Repeat screening SBP at visit 1 129+/-129+/-

8 mm Hg8 mm HgSBP at visit 2 123+/-7 mm Hg SBP at visit 2 123+/-7 mm Hg SBP at visit 3 121+/-8 mm HgSBP at visit 3 121+/-8 mm Hg

Screening termination occurred in 15% Screening termination occurred in 15% with isolated SBP hypertensionwith isolated SBP hypertension

Am J Hypertens. 2001 Aug;14(8 Pt 1):783-7.Am J Hypertens. 2001 Aug;14(8 Pt 1):783-7.

ABPMABPM

Ambulatory blood pressure monitors Ambulatory blood pressure monitors New technologyNew technologyMeasure blood pressure every 15 minutes Measure blood pressure every 15 minutes

while awakewhile awakeMeasure blood pressure every 30 minutes Measure blood pressure every 30 minutes

while asleepwhile asleepNight time blood pressure drops 10% Night time blood pressure drops 10%

normallynormally

0 3 6 9 12 15 18 21 24100

120

140

160

180

Awake SBPload = 80%

Sleep SBPload = 60%

Time of Day

Example of ABPMExample of ABPM

ABPMABPM

American Journal of Kidney Diseases (1999) 33: 667-674

ABPMABPM

30% of patients with office hypertension 30% of patients with office hypertension have normal blood pressures by ABPMhave normal blood pressures by ABPM

White Coat HypertensionWhite Coat HypertensionIncidence reported from 31-50%Incidence reported from 31-50%

Hornsby: J Fam Prac 1991;33:617-23Hornsby: J Fam Prac 1991;33:617-23Reusz: Arch Dis Child 1994;70:90-4Reusz: Arch Dis Child 1994;70:90-4Lingens: Ped Neph 1995;9:167-72Lingens: Ped Neph 1995;9:167-72Gillerman: Ped Neph 1997;11:707-10Gillerman: Ped Neph 1997;11:707-10

White Coat HypertensionWhite Coat Hypertension

These patients do not need a work upThese patients do not need a work upObviously there are significant financial Obviously there are significant financial

and psychosocial incentives for identifying and psychosocial incentives for identifying these patients.these patients.The workup is expensiveThe workup is expensiveChronic medication is expensiveChronic medication is expensive

Hypertension Less than 1 Year OldHypertension Less than 1 Year Old

Age GroupAge Group Most CommonMost Common Less CommonLess Common

Infants and NeonatesInfants and Neonates Renal artery Renal artery thrombosis after thrombosis after umbilical artery umbilical artery catheterizationcatheterization

Bronchopulmonary Bronchopulmonary DysplasiaDysplasia

Coarctation of the Coarctation of the aortaaorta

Patent ductus Patent ductus arteriosusarteriosus

Congenital renal Congenital renal diseasedisease

Intraventricular Intraventricular hemorrhagehemorrhage

Renal artery stenosisRenal artery stenosis Neurogenic tumorsNeurogenic tumors

Causes of HypertensionCauses of HypertensionAge GroupAge Group Most CommonMost Common Less CommonLess Common1-101-10 Renal DiseaseRenal Disease Renal artery stenosisRenal artery stenosis

Coarctation of the aortaCoarctation of the aorta HypercalcemiaHypercalcemiaEssentialEssential NeurofibromatosisNeurofibromatosis

PheochromocytomaPheochromocytomaPrimary hyperaldosteronismPrimary hyperaldosteronism1111ββ hydroxylase deficiency hydroxylase deficiency1717αα hydroxylase deficiency hydroxylase deficiencyApparent mineralocorticoid excessApparent mineralocorticoid excessLiddle’s syndromeLiddle’s syndromeGlucocorticoid remediable Glucocorticoid remediable hypertensionhypertensionHypertension induced by Hypertension induced by immobilizationimmobilizationSleep apnea associated hypertensionSleep apnea associated hypertensionHead trauma associatedHead trauma associated

11 and older11 and older Renal DiseaseRenal Disease All diagnosis listed aboveAll diagnosis listed aboveEssential hypertensionEssential hypertension

Typical WorkupTypical Workup

Renal PanelRenal PanelPlasma Aldosterone/Renin Plasma Aldosterone/Renin Urine analysisUrine analysisUrine protein/creatinineUrine protein/creatinineRenal ultrasoundRenal ultrasound4 point blood pressure readings 4 point blood pressure readings CBCCBCTSHTSH

Renal PanelRenal Panel

Low potassium, High bicarbonateLow potassium, High bicarbonateHigh potassium, Low BicarbonateHigh potassium, Low BicarbonateRenal FunctionRenal FunctionCalcium levelCalcium level

Hypokalemic Metabolic AlkalosisHypokalemic Metabolic Alkalosis

HyperaldosteronismHyperaldosteronismLiddle’s SyndromeLiddle’s SyndromeApparent Mineralocorticoid ExcessApparent Mineralocorticoid ExcessGlucocorticoid Remediable HypertensionGlucocorticoid Remediable HypertensionRenal Artery StenosisRenal Artery StenosisReninomaReninoma

Mechanism of Hypokalemia and Mechanism of Hypokalemia and Metabolic AlkalosisMetabolic Alkalosis

Aldosterone Aldosterone increases ENaC increases ENaC densitydensity

Negative luminal Negative luminal charge developscharge develops

K+ and H+ secreted K+ and H+ secreted to maintain to maintain electroneutralityelectroneutrality

We don’t PEE We don’t PEE LIGHTNINGLIGHTNING

Liddle’s SyndromeLiddle’s Syndrome

Gain of function abnormality of ENaCGain of function abnormality of ENaCResults in sodium retentionResults in sodium retentionLow levels of aldosteroneLow levels of aldosteroneFormerly known as Formerly known as

pseudohyperaldosteronismpseudohyperaldosteronism

Apparent Mineralocorticoid ExcessApparent Mineralocorticoid Excess

Mutation in gene encoding for 11Mutation in gene encoding for 11ββ hydroxysteroid dehydrogenasehydroxysteroid dehydrogenaseCortisol is not converted to cortisone Cortisol is not converted to cortisone

intracellularlyintracellularlyCortisol binds to the mineralocorticoid Cortisol binds to the mineralocorticoid

receptor because the concentration is 100 receptor because the concentration is 100 times greater than mineralocorticoidstimes greater than mineralocorticoids

Mineralocorticoid receptors are activated Mineralocorticoid receptors are activated by cortisolby cortisol


Associated withAssociated withLicoriceLicoriceChewing tobaccoChewing tobaccoCarbenoxolone Carbenoxolone

Glycyrrhetinic acid is the active componentGlycyrrhetinic acid is the active componentLow reninLow reninLow aldosterone levelLow aldosterone levelAutosomal RecessiveAutosomal Recessive


Mineralocorticoid Receptor

Normal Cortisol

11β-hydroxysteroid dehydrogenase Type 2

Corticosterone

Aldosterone

Cortisol

11β-hydroxysteroid dehydrogenase Type 2

Corticosterone

Cortisol Mineralocorticoid Receptor

AME

Glucocorticoid Remediable Glucocorticoid Remediable HypertensionHypertension

Duplication of genes encoding aldosterone Duplication of genes encoding aldosterone synthase and 11synthase and 11ββ hydroxylase hydroxylase

Ectopic production of aldosterone occurs Ectopic production of aldosterone occurs under ACTH controlunder ACTH control

Glucorticoid Remediable Glucorticoid Remediable HypertensionHypertension

Glomerulosa Fasciculata

Progesterone ProgesteroneProgesterone

Deoxycorticosterone Deoxycorticosterone17 hydroxyprogesterone

CYP11β1 CYP11β1

CorticosteroneCorticosterone 11-deoxycortisol

CYP11β1

Cortisol

18-hydroxycorticosterone18-hydroxycorticosterone

CYP11β2Chimeric CYP11β2

Aldosterone Aldosterone

Hyperkalemic Metabolic AcidosisHyperkalemic Metabolic Acidosis

Gordon’s SyndromeGordon’s SyndromeAKA Pseudohypoaldosteronism Type 2AKA Pseudohypoaldosteronism Type 2Gain of function of the thiazide sodium Gain of function of the thiazide sodium

chloride cotransporterchloride cotransporterAutosomal dominantAutosomal dominant

Renal FunctionRenal Function

Normal ValuesNormal Values1 – 5 years old1 – 5 years old 0.3-0.5 mg/dL0.3-0.5 mg/dL6-11 years old6-11 years old 0.5-0.7 mg/dL0.5-0.7 mg/dLGirls > 11 yearsGirls > 11 years 0.7-0.9 mg/dL0.7-0.9 mg/dLBoys > 11 yearsBoys > 11 years 0.7-1.2 mg/dL0.7-1.2 mg/dL

Normal creatinine is determined by the Normal creatinine is determined by the muscle mass of the patient and their renal muscle mass of the patient and their renal functionfunction

Renal FunctionRenal Function

Schwartz EquationSchwartz Equation

CreCL = constant * Height / creatinineCreCL = constant * Height / creatinine

ConstantConstant 0.25 micropremie0.25 micropremie 0.33 Term neonate0.33 Term neonate 0.45 Infants0.45 Infants 0.55 Children 1-12, Adolescent girls 0.55 Children 1-12, Adolescent girls 0.70 Adolescent boys >120.70 Adolescent boys >12

Urine AnalysisUrine Analysis

HematuriaHematuriaGlomerular diseaseGlomerular disease

PyuriaPyuria Interstitial nephritisInterstitial nephritis

ProteinuriaProteinuriaGlomerular diseaseGlomerular diseaseHyperfiltration syndromeHyperfiltration syndromeReflux nephropathyReflux nephropathy

Red Blood Cell CastRed Blood Cell Cast

Urine Protein/CreatinineUrine Protein/Creatinine

More sensitive than albustix in detecting More sensitive than albustix in detecting proteinuriaproteinuria

Microalbumin detection sticks can be usedMicroalbumin detection sticks can be used

Renal UltrasoundRenal Ultrasound

Urologic abnormalitiesUrologic abnormalitiesUreteropelvic junction obstructionUreteropelvic junction obstructionMulticystic dysplastic kidneysMulticystic dysplastic kidneys

Polycystic kidney diseasePolycystic kidney diseaseRenal scarringRenal scarringDiscordant kidney size Discordant kidney size

Reflux nephropathyReflux nephropathyRenal artery stenosisRenal artery stenosis

4 Extremity BP4 Extremity BP

Screen for coarctationScreen for coarctationNot 100% sensitiveNot 100% sensitiveEchocardiogram is the diagnostic test of Echocardiogram is the diagnostic test of

choicechoice

If Workup is Negative?If Workup is Negative?

Start treatment with antihypertensive Start treatment with antihypertensive medication under the following medication under the following circumstancescircumstancesComorbid conditionsComorbid conditionsEvidence of end organ damageEvidence of end organ damage

Echocardiogram with LVHEchocardiogram with LVH

Systolic blood pressure 10 mm Hg greater Systolic blood pressure 10 mm Hg greater than 95%than 95%

Failure of lifestyle modificationsFailure of lifestyle modifications

Lifestyle ModificationsLifestyle Modifications

Salt restrictionSalt restrictionExercise 20 minutes 5 days a weekExercise 20 minutes 5 days a week

HR should achieve 85% of maximumHR should achieve 85% of maximumWeight lossWeight loss

Lifestyle ModificationsLifestyle Modifications

Why don’t they work?Why don’t they work?Entire family needs to participateEntire family needs to participateTime is an issueTime is an issue

CookingCookingExerciseExercise

Parents are frequently obeseParents are frequently obese

When to Perform More TestingWhen to Perform More Testing

Any abnormality of primary screeningAny abnormality of primary screeningAldosterone/Renin > 30Aldosterone/Renin > 30

HyperaldosteronismHyperaldosteronism

Abnormal Urine analysisAbnormal Urine analysisDiscordant kidney sizeDiscordant kidney sizeSevere hypertensionSevere hypertensionFamily historyFamily history

NF, MENNF, MENEarly strokes in familyEarly strokes in family

Renal Artery Stenosis?Renal Artery Stenosis?

Usually renin and aldosterone elevatedUsually renin and aldosterone elevatedMore than 1 medications required for BP More than 1 medications required for BP

controlcontrol20% incidence of RAS20% incidence of RAS

BP greater than 99%BP greater than 99%43% incidence of RAS43% incidence of RAS

Pediatr Nephrol. 2000 Aug;14(8-9):816-9.

Renal Scan And AngiogramRenal Scan And Angiogram

RAS on AngiogramRAS on Angiogram

Screen for Pheochromocytoma?Screen for Pheochromocytoma?

Family history of pheochromocytomaFamily history of pheochromocytoma MENMEN von Hippel Lindauvon Hippel Lindau Neurofibromatosis is unlikely to be associated with Neurofibromatosis is unlikely to be associated with

pheochromocytoma prior to age 25pheochromocytoma prior to age 25

SymptomsSymptoms FlushingFlushing HeadachesHeadaches ParoxysmsParoxysms TachycardiaTachycardia

Testing for PheochromocytomaTesting for Pheochromocytoma

No pediatric normal valuesNo pediatric normal valuesMetanepherines are higher in childrenMetanepherines are higher in children

Biochemical Biochemical testtest

SensitivitySensitivity SpecificitySpecificity Sensitivity at Sensitivity at 100% 100% SpecificitySpecificity

Plasma Plasma MetanepherineMetanepherine

9999 8989 8282

Plasma Plasma CatecholamineCatecholamine

8585 8080 3838

Urinary Urinary CatecholamineCatecholamine

8383 8888 6464

Urinary Urinary MetanepherineMetanepherine

7676 9494 5353

Urinary VMAUrinary VMA 6363 9494 4343

Ann Intern Med, Feb 2001; 134: 315 - 329.

Testing for PheochromocytomaTesting for Pheochromocytoma

Plasma metanepherines is the best screenPlasma metanepherines is the best screenSend out to Mayo clinicSend out to Mayo clinic

Hypertension in office

Correct size cuff Wait 5 minutes and repeat Still high Check 2 more visits

Home BP Monitoring Ambulatory BPM

BP Normal

White Coat HTN

BP Abnormal

Family History Physical Exam CBC Urine Analysis Renal Panel Aldosterone/Renin Urine Protein/creatinine

Comorbid Conditions Diabetes, Renal Disease, Cardiac Disease, Obesity

Treat with Antihypertensives

No Comorbid Conditions

Lifestyle Modifications

Consider Echocardiogram

No LVH

LVH Present

HTN after 1 year

HTN Resolved

BP check every 6 months

Workup Negative

Workup Positive Treat

Why No EKG?Why No EKG?

Sensitivity < 20% to detect LVHSensitivity < 20% to detect LVHSpecificity 88% to detect LVHSpecificity 88% to detect LVHEKG is a poor screening test for LVHEKG is a poor screening test for LVH

If the EKG demonstrates LVH criteria the If the EKG demonstrates LVH criteria the patient likely has LVHpatient likely has LVH

Am Heart J. 2003 Apr;145(4):716-23.

Medication AlgorithmMedication AlgorithmHypertension

IHSS Renal DiseaseNo ComorbiditiesObesity

Beta Blocker

Cardizem

ACE Inhibitor

ACE Inhibitor

Angiotensin Receptor Blocker

Diuretic

Calcium Channel Blocker

ACE Inhibitor


Second Calcium Channel Blocker

Diuretic



ACE Inhibitor


Angiotensin Receptor Blocker

Calcium Channel BlockersCalcium Channel Blockers

AmlodipineAmlodipineStudied in childrenStudied in children54 hour half life54 hour half life

Missing a dose is not an issueMissing a dose is not an issueOnce a day dosingOnce a day dosingDrops BP effectivelyDrops BP effectively

CardizemCardizemOnce daily dosingOnce daily dosingNegative ionotropeNegative ionotrope

ACE InhibitorsACE Inhibitors

LisinoprilLisinoprilGeneric- 7 dollars a monthGeneric- 7 dollars a monthOnce daily doseOnce daily dosePediatric studiesPediatric studies

CaptoprilCaptopril3 times a day3 times a day

VasotecVasotec2 times a day2 times a day

ACE Inhibitors CautionACE Inhibitors Caution

Nephrogenesis occurs until 2 years of ageNephrogenesis occurs until 2 years of ageACE Inhibitors decrease TGF-ACE Inhibitors decrease TGF-ββ and TNF- and TNF-

αα expression expressionThis may lead to a decrease in nephron This may lead to a decrease in nephron

massmass

Consider not using ACE Inhibitors until Consider not using ACE Inhibitors until after 2 years of ageafter 2 years of age

Angiotensin Receptor BlockersAngiotensin Receptor Blockers

All have been studied in childrenAll have been studied in children IrbesartanIrbesartanCandesartanCandesartanLosartanLosartanTelmesartanTelmesartan

ConclusionConclusion

Hypertension in children is increasing in Hypertension in children is increasing in incidenceincidence

Most children have essential hypertensionMost children have essential hypertensionThe workup is simple and inexpensiveThe workup is simple and inexpensiveAngiogram indicated for severe Angiogram indicated for severe

hypertensionhypertensionPlasma metanepherines is the best screen Plasma metanepherines is the best screen

for pheochromocytomafor pheochromocytomaOnce a day medications for complianceOnce a day medications for compliance

Health & Medicine

Pediatric Hypertension Nephrologist View