Cardiovascular

complications

of

pediatric

chronic

kidney

disease

Cardiovascular

disease

-LRB-

CVD

-RRB-

mortality

is

a

leading

cause

of

death

in

adult

chronic

kidney

disease

-LRB-

CKD

-RRB-

with

exceptionally

high

rates

in

young

adults

according

to

the

Task

Force

on

Cardiovascular

Disease

Recent

data

indicate

that

cardiovascular

complications

are

already

present

in

children

with

CKD

This

review

summarizes

the

current

literature

on

cardiac

risk

factors

mortality

and

morbidity

in

children

with

CKD

Learning

objectives

To

review

recent

data

on

the

epidemiology

of

CVD

in

children

with

CKD

To

understand

the

mechanisms

of

cardiovascular

abnormalities

in

pediatric

CKD

To

review

recent

advances

in

the

diagnosis

and

clinical

presentation

of

cardiovascular

complications

in

children

with

CKD

To

outline

current

understanding

in

the

strategies

to

prevent

progression

of

CVD

in

children

with

CKD

Cardiovascular

mortality

and

morbidity

The

survival

of

children

with

CKD

in

the

U.S.

remains

low

for

children

on

dialysis

the

lifespan

is

years

less

and

for

transplant

patients

about

years

less

than

that

of

an

age

and

race-matched

US

population

-LSB-

-RSB-

The

most

likely

cause

of

this

is

increased

cardiovascular

mortality

due

to

the

development

of

accelerated

ischemic

heart

disease

and

premature

dilated

cardiomyopathy

The

evidence

comes

from

studies

of

young

adults

who

developed

renal

failure

during

childhood

Oh

et

al.

-LSB-

-RSB-

analyzed

the

outcome

of

young

adults

with

childhood

onset

CKD

between

and

Fifty

percent

of

the

deceased

patients

had

died

of

cardiovascular

or

cerebrovascular

events

Groothoff

et

al.

-LSB-

-RSB-

conducted

a

national

retrospective

and

prospective

cross-sectional

study

to

evaluate

the

late

physical

social

and

psychological

effects

of

renal

insufficiency

-LRB-

LERIC

-RRB-

in

all

Dutch

children

who

started

renal

replacement

therapy

between

and

Of

patients

had

died

Cardiovascular

disease

was

the

most

common

cause

of

death

and

accounted

for

of

all

deaths

Cerebrovascular

accident

congestive

heart

failure

myocardial

infarction

and

cardiac

arrest

-LRB-

respectively

-RRB-

were

the

most

common

causes

of

cardiac

death

Similar

analysis

of

long-term

survival

from

the

Australia

and

New

Zealand

Dialysis

and

Transplant

Registry

-LSB-

-RSB-

of

all

children

and

adolescents

who

were

under

years

of

age

when

renal

replacement

therapy

commenced

-LRB-

study

period

was

years

-RRB-

showed

mortality

rates

times

higher

than

in

the

age-matched

general

population

CVD

was

the

most

common

cause

of

death

-LRB-

-RRB-

Cardiovascular

death

happens

not

only

in

later

life

but

also

in

childhood

CKD

In

the

general

pediatric

population

the

incidence

of

annual

death

due

to

cardiac

disease

is

less

than

Yet

annual

reports

from

the

United

States

Renal

Data

System

-LRB-

USRDS

-RRB-

indicate

that

over

the

last

decade

CVD

has

remained

the

second

most

common

cause

of

death

in

children

on

chronic

dialysis

or

after

transplantation

accounting

for

approximately

of

all

deaths

Parekh

et

al.

-LSB-

-RSB-

using

the

USRDS

database

performed

a

detailed

cross-sectional

analysis

to

evaluate

the

risk

of

a

cardiac

death

in

children

and

young

adults

-LRB-

age

years

-RRB-

and

to

identify

factors

potentially

associated

with

CVD

mortality

A

total

of

deaths

between

and

were

analyzed

There

were

cardiac

deaths

-LRB-

of

the

total

-RRB-

Cardiac

deaths

in

children

and

young

adults

in

whom

ESRD

developed

during

childhood

were

approximately

times

more

frequent

than

in

the

general

pediatric

population

Of

the

specific

categories

of

cardiovascular

deaths

cardiac

arrest

was

the

most

common

cause

in

each

of

the

age

groups

followed

by

arrhythmia

and

cardiomyopathy

These

causes

of

cardiac

death

are

different

from

those

of

adults

In

adults

coronary

artery

disease

and

chronic

congestive

heart

failure

are

the

leading

causes

of

CVD

mortality

and

as

shown

by

Parekh

et

al.

-LSB-

-RSB-

these

causes

are

extremely

rare

in

children

and

adults

younger

than

years

of

age

The

incidence

of

cardiac

arrest

in

the

youngest

age

group

-LRB-

years

-RRB-

was

five

to

ten

times

higher

than

in

other

age

groups

perhaps

as

noted

by

the

authors

a

reflection

of

the

difficulty

of

ascertaining

the

true

cause

of

death

in

young

children

Some

of

these

young

children

might

have

died

from

other

co-morbid

conditions

such

as

congenital

disorders

that

are

not

included

in

the

USRDS

database

The

high

rate

of

sudden

death

in

children

especially

in

infants

with

ESRD

is

poorly

understood

and

warrants

further

investigation

In

adults

sudden

death

is

often

a

result

of

fatal

arrhythmias

due

to

acute

ischemia

of

preexisting

atherosclerotic

disease

It

is

believed

that

arrhythmias

are

also

the

likely

cause

of

most

cases

of

sudden

cardiac

death

-LRB-

SCD

-RRB-

in

children

However

the

origin

of

acquired

malignant

arrhythmias

in

children

is

unlikely

to

be

an

atherosclerotic

lesion

Dilated

especially

hypertrophic

cardiomyopathies

are

a

leading

cause

of

SCD

in

children

-LSB-

-RSB-

The

macroscopic

and

microscopic

structural

abnormalities

in

cardiomyopathies

involve

fibrosis

and

cellular

hypertrophy

prone

to

produce

an

electrical

instability

with

resultant

arrhythmias

Ischemia

of

small

coronary

vessel

disease

secondary

to

medial

hypertrophy

might

result

in

dispersion

of

repolarization

properties

and

arrhythmia

from

re-entrant

or

autonomic

mechanisms

As

we

discuss

in

more

detail

below

in

this

review

children

with

CKD

develop

left

ventricular

hypertrophy

-LRB-

LVH

-RRB-

which

is

frequently

severe

especially

in

children

on

prolonged

dialysis

therapy

-LSB-

-RSB-

It

is

currently

unknown

if

LVH

in

young

patients

with

CKD

is

characterized

by

structural

abnormalities

similar

to

familial

or

idiopathic

hypertrophic

cardiomyopathies

associated

with

SCD

Whether

LVH

of

children

with

ESRD

can

contribute

to

increased

SCD

is

also

not

known

Another

possibility

for

deadly

arrhythmias

in

children

with

ESRD

is

acute

changes

in

the

cardiac

extra

or

intracellular

ionic

milieu

especially

involving

abnormalities

of

sodium

and

potassium-based

repolarization

currents

Because

the

causes

of

cardiac

death

in

children

and

adults

are

different

it

is

not

surprising

that

of

the

traditional

or

uremia-related

risk

factors

for

adult

atherosclerotic

CVD

predicted

cardiac

death

in

the

study

by

Parekh

-LSB-

-RSB-

One

of

the

examples

presented

in

this

paper

is

the

effect

of

race

on

CVD

death

In

adults

with

ESRD

white

males

are

at

higher

risk

for

CVD

mortality

In

contrast

black

children

as

shown

by

Parekh

et

al.

-LSB-

-RSB-

appear

to

have

an

increased

risk

for

cardiac

death

Another

important

observation

of

this

study

is

that

transplant

recipients

had

lower

risk

of

cardiac

death

than

dialysis

patients

However

the

authors

pointed

out

that

the

CVD

mortality

rate

in

transplanted

patients

was

still

significantly

higher

-LRB-

approximately

ten

times

-RRB-

than

in

the

general

pediatric

population

The

analysis

of

cardiac

morbidity

in

children

on

chronic

dialysis

performed

by

Chavers

et

al.

-LSB-

-RSB-

has

confirmed

that

cardiac

disease

in

children

is

different

from

adults

A

total

of

Medicare

incident

pediatric

-LRB-

years

-RRB-

dialysis

patients

were

identified

from

to

Among

them

-LRB-

-RRB-

developed

a

cardiac-related

event

Arrhythmia

was

most

common

-LRB-

-RRB-

followed

by

valvular

disease

-LRB-

-RRB-

cardiomyopathy

-LRB-

-RRB-

and

cardiac

arrest

-LRB-

-RRB-

Ischemic

heart

disease

was

extremely

rare

in

these

children

Risk

factors

for

cardiovascular

disease

The

risk

factors

and

pathogenic

mechanisms

of

development

of

CVD

in

young

adults

who

had

onset

of

CKD

in

childhood

are

better

understood

than

are

those

producing

cardiac

morbidity

and

mortality

in

children

The

conventional

thinking

is

that

two

groups

of

risk

factors

are

responsible

for

accelerated

CVD

in

adults

with

CKD

-LRB-

Table

-RRB-

Table

risk

factors

in

chronic

kidney

disease

in

adultsTraditionalCKD-relatedOlder

ageDecreased

GFRWhite

raceProteinuriaMale

genderPeripheral

renin-angiotensin-aldosterone

activityHypertensionAbnormal

calcium

and

phosphorus

LDL

CholesterolDyslipidemia

HDL

CholesterolHypoalbuminemiaDiabetes

mellitusHemodynamic

overloadTobacco

useAnemiaPhysical

inactivityThrombogenic

factorsPsychosocial

stressHyperhomocysteinemiaFamily

history

of

CVDOxidative

stressLVHInfection

-LRB-

Chlamydia

pneumoniae

-RRB-

ObesityChronic

inflammation

First

as

compared

to

the

non-uremic

population

there

is

an

over-representation

in

uremic

patients

of

classical

risk

factors

e.g.

diabetes

hypertension

and

hyperlipidemia

A

majority

of

the

adults

who

develop

ESRD

do

so

as

a

complication

of

diabetes

or

generalized

atherosclerosis

Often

cardiac

disease

antedates

the

onset

of

CKD

in

these

patients

Unfortunately

children

with

CKD

share

with

adults

a

similar

high

prevalence

of

risk

factors

for

adult-type

atherosclerotic

CVD

It

is

also

troubling

that

the

frequencies

of

these

traditional

risk

factors

have

not

changed

over

last

decade

The

North

American

Pediatric

Renal

Trials

Collaborative

Studies

-LRB-

NAPRTCS

-RRB-

data

demonstrate

that

hypertension

develops

at

early

stages

of

CKD

-LRB-

-RRB-

and

persists

-LRB-

-RRB-

in

uremic

children

-LSB-

-RSB-

Dyslipidemia

is

found

in

to

during

chronic

dialysis

-LSB-

-RSB-

Successful

renal

transplantation

leads

to

a

dramatic

improvement

in

renal

function

and

elimination

of

many

risk

factors

for

atherosclerotic

CVD

that

were

present

while

on

dialysis

However

transplant

recipients

are

not

free

from

multiple

complications

and

transplantation

may

amplify

some

of

the

traditional

risk

factors

Indeed

the

prevalence

of

hypertension

in

pediatric

renal

allograft

recipients

is

between

-LSB-

-RSB-

Also

hyperlipidemia

may

not

disappear

after

renal

transplantation

the

reported

prevalence

is

above

-LSB-

-RSB-

The

NAPRTCS

data

also

show

that

the

rate

of

obesity

another

CV

risk

is

increasing

in

children

with

ESRD

at

the

time

of

transplantation

-LRB-

after

vs.

prior

to

-RRB-

-LSB-

-RSB-

Single-center

study

data

indicate

that

the

number

of

obese

patients

can

double

at

year

after

transplantation

-LSB-

-RSB-

Second

there

is

a

multitude

of

uremia-related

risk

factors

for

atherosclerotic

CVD

In

adults

with

CKD

an

increased

homocysteine

level

appeared

to

be

an

independent

risk

factor

for

CVD

morbidity

and

mortality

-LSB-

-RSB-

Anemia

has

been

linked

to

negative

CVD

outcome

-LSB-

-RSB-

Hyperphosphatemia

with

increased

calcium-phosphorus

product

constitutes

a

risk

for

cardiovascular

calcification

cardiac

ischemia

and

adverse

cardiovascular

outcomes

-LSB-

-RSB-

Elevated

serum

C-reactive

protein

-LRB-

CRP

-RRB-

a

marker

of

systemic

inflammation

has

been

found

to

be

a

strong

predictor

of

cardiac

morbidity

and

cardiac

death

in

CKD

patients

-LSB-

-RSB-

Another

marker

of

inflammation

has

been

associated

with

increased

cardiac

morbidity

in

adults

with

CKD

-LSB-

-RSB-

The

role

of

systemic

inflammation

in

CKD

has

been

reviewed

recently

elsewhere

-LSB-

-RSB-

Inflammation

is

directly

linked

to

oxidative

stress

which

is

now

considered

as

a

hallmark

of

uremia

-LSB-

-RSB-

Asymmetric

dimethylarginine

-LRB-

ADMA

-RRB-

an

endogenous

inhibitor

of

nitric

oxide

synthase

and

a

marker

of

oxidative

stress

has

been

extensively

evaluated

in

patients

with

CKD

by

Zoccali

et

al.

-LSB-

-RSB-

The

authors

demonstrated

that

elevated

ADMA

per

se

was

responsible

for

a

higher

risk

of

death

and

for

a

higher

risk

of

cardiovascular

events

in

dialysis

patients

-LSB-

-RSB-

Another

subset

of

novel

CVD

risk

factors

is

adipokines

Adipokines

leptin

and

adiponectin

are

the

products

of

adipose

tissue

involving

in

regulation

of

lipid

and

glucose

metabolism

Abnormal

adipokines

are

strongly

linked

to

insulin

resistance

a

known

CV

risk

in

CKD

-LSB-

-RSB-

It

has

been

determined

that

lower

plasma

adiponectin

concentration

independently

predicts

increased

CVD

morbidity

and

mortality

in

adults

with

ESRD

-LSB-

-RSB-

Clinical

Practice

Guidelines

for

Cardiovascular

Disease

in

Dialysis

Patients

extensively

reviewed

the

current

literature

on

CVD

biomarkers

and

the

reader

is

referred

to

this

publication

for

more

information

-LSB-

-RSB-

As

in

adults

in

children

with

CKD

many

of

these

risk

factors

are

very

prevalent

-LRB-

Table

-RRB-

Table

of

risk

factors

for

CVD

in

children

with

CKDRisk

factorsCRIa

-LRB-

-RRB-

Dialysisb

-LRB-

-RRB-

Transplantc

-LRB-

-RRB-

b

c

cHypoalbuminemia

Recent

studies

in

adults

on

chronic

hemodialysis

place

a

malnutrition-inflammation

complex

at

the

center

of

a

debate

about

the

role

of

traditional

and

non-traditional

risk

factors

for

poor

cardiovascular

outcome

This

issue

emerged

after

publication

of

a

series

of

articles

summarized

in

the

review

by

Nurmohamed

and

Nube

-LSB-

-RSB-

describing

the

phenomenon

of

reverse

epidemiology

The

studies

have

shown

that

in

adults

on

chronic

hemodialysis

low

blood

pressure

low

body

mass

index

-LRB-

BMI

-RRB-

low

serum

cholesterol

and

low

serum

homocysteine

are

often

correlated

with

an

unfavorable

clinical

outcome

Thus

whereas

traditional

risk

factors

of

CVD

are

correlated

with

an

unfavorable

outcome

in

the

general

population

and

patients

with

CKD

not

yet

on

dialysis

in

hemodialyzed

patients

mild

hypertension

hypercholesterolemia

and

being

overweight

appear

to

be

protective

and

associated

with

an

improved

survival

It

has

been

speculated

that

a

malnutrition-inflammation-atherosclerosis

complex

underlies

at

least

partly

the

phenomenon

of

reverse

epidemiology

since

malnutrition

causes

a

low

BMI

hypocholesterolemia

and

low

serum

homocysteine

levels

Mechanisms

of

cardiovascular

disease

in

chronic

kidney

disease

There

are

two

parallel

processes

involved

in

the

development

of

CVD

in

CKD

patients

-LRB-

Fig.

-RRB-

Fig.

disease

in

chronic

kidney

disease

The

first

is

cardiac

remodeling

leading

to

hypertrophy

of

the

left

ventricle

-LRB-

LV

-RRB-

as

a

response

to

mechanical

or

hemodynamic

overload

Two

different

patterns

of

LV

remodeling

can

produce

increase

in

LV

mass

-LRB-

LVM

-RRB-

-LSB-

-RSB-

The

concentric

LV

remodeling

and

hypertrophy

may

be

the

results

of

pressure

overload

as

occurs

with

hypertension

whereas

eccentric

LVH

may

be

related

to

volume

and

sodium

retention

anemia

and

arteriovenous

shunt

The

patterns

of

sarcomere

formation

induced

by

pressure

or

volume

overload

are

distinct

Pressure-induced

concentric

LVH

is

characterized

by

a

parallel

addition

of

sarcomeres

resulting

in

the

increase

of

cross-sectional

area

and

diameter

of

the

myocytes

Increase

in

LVM

in

this

case

is

obtained

by

a

marked

increase

in

wall

thickness

with

a

less

evident

increase

in

the

LV

cavity

that

yields

an

elevated

relative

wall

thickness

and

concentric

LVH

From

the

physiological

view

increased

systolic

blood

pressure

-LRB-

BP

-RRB-

and

pulse

pressure

due

to

increased

peripheral

resistance

and

arterial

stiffness

are

the

principal

factors

opposing

LV

ejection

and

leading

to

an

increased

LV

workload

and

concentric

LVH

An

increase

in

LVM

can

also

be

obtained

by

an

increase

in

the

LV

cavity

with

a

symmetric

increase

in

wall

thickness

to

maintain

the

ratio

between

the

wall

thickness

and

LV

transversal

radius

-LRB-

relative

wall

thickness

-RRB-

normal

producing

eccentric

LVH

In

this

case

the

addition

of

sarcomeres

occurs

mainly

in

series

resulting

in

longitudinal

cell

growth

In

the

transition

to

maladaptive

LVH

LV

dilatation

becomes

disproportional

to

wall

thickness

with

myocytes

elongated

without

an

increase

in

diameter

Experimental

models

of

cardiac

hypertrophy

support

the

theory

that

mechanical

stress

due

to

either

pressure

or

volume

overload

is

a

trigger

for

activation

of

other

multiple

mechanisms

leading

to

myocardial

remodeling

-LSB-

-RSB-

These

factors

include

a

local

overexpression

of

the

renin-angiotensin-aldosterone

system

-LRB-

RAAS

-RRB-

adrenergic

system

inflammatory

cytokines

and

other

autocrine

and

paracrine

mechanisms

In

patients

with

CKD

these

mechanisms

might

be

activated

independently

of

hemodynamic

overload

since

uremia

per

se

is

associated

with

an

alteration

in

multiple

humoral

factors

-LSB-

-RSB-

With

time

a

maladaptive

phase

of

LVH

develops

characterized

by

decreased

capillary

density

decreased

coronary

reserve

and

subendocardial

perfusion

a

tendency

to

arrhythmia

and

the

development

of

myocardial

fibrosis

All

this

leads

to

myocyte

death

and

finally

to

diastolic

and

systolic

dysfunction

The

second

process

involves

vascular

injury

Exposure

to

CV

risk

factors

results

in

vascular

changes

including

atherosclerotic

and

arteriosclerotic

processes

and

vascular

calcification

Atherosclerosis

refers

to

the

process

of

plaque

formation

or

atheroma

development

The

process

of

atheroma

formation

begins

with

an

accumulation

of

lipid-containing

foam

cells

-LRB-

macrophages

-RRB-

in

the

vascular

intima

and

evolves

into

successive

structures

that

penetrate

the

vascular

wall

and

include

lipids

smooth

muscle

cells

and

collagen

fibers

-LSB-

-RSB-

Calcification

is

an

intrinsic

part

of

the

process

and

generally

involves

the

intima

Atherosclerotic

lesions

have

a

patchy

distribution

along

the

length

of

the

artery

and

cause

local

stenoses

and

occlusions

Recently

endothelial

progenitor

cells

-LRB-

EPCs

-RRB-

have

been

identified

as

contributing

to

angiogenesis

-LSB-

-RSB-

The

EPC

number

has

been

shown

to

be

reduced

in

patients

with

CVD

leading

to

speculation

that

atherosclerosis

may

be

caused

by

a

consumptive

loss

of

the

endothelial

repair

capacity

Animal

experiments

have

shown

that

EPCs

reendothelialise

injured

vessels

and

that

this

reduces

neointimal

formation

confirming

that

EPCs

have

an

atheroprotective

effect

Arteriosclerosis

is

arterial

stiffening

involving

the

entire

arterial

tree

although

it

principally

affects

the

elastic

arteries

Unlike

atherosclerosis

arteriosclerosis

involves

both

intimal

and

medial

thickening

In

CKD

arteriosclerosis

can

occur

in

the

absence

of

significant

atherosclerotic

disease

-LSB-

-RSB-

Arteriosclerosis

is

associated

with

vascular

remodeling

characterized

by

increased

wall

thickness

lumen

enlargement

and

increased

length

of

arteries

This

leads

to

an

increase

of

systolic

BP

and

pulse

pressure

and

arterial

stiffening

The

triggers

for

vascular

calcification

are

complex

and

include

metabolic

mechanical

infectious

and

inflammatory

injuries

Increased

calcium

x

phosphate

ion

product

or

hyperphosphatemia

may

be

the

key

promoter

of

vascular

calcification

-LSB-

-RSB-

The

mechanisms

include

either

stimulation

of

the

uptake

and

precipitation

of

calcium

and

phosphate

into

the

vessel

or

a

decrease

of

the

inhibitory

process

that

prevents

these

ions

from

precipitation

Fetuin-A

the

anti-inflammatory

protein

is

a

highly

potent

inhibitor

of

serum

calcium-phosphate

complex

formation

-LSB-

-RSB-

The

serum

concentrations

of

Fetuin-A

are

decreased

in

ESRD

patients

-LSB-

-RSB-

Another

promoter

of

vascular

calcification

is

-LRB-

OH

-RRB-

which

may

have

a

direct

effect

on

the

calcium

deposition

in

vascular

smooth

muscle

cells

-LSB-

-RSB-

In

a

comprehensive

review

Vattikuti

and

Towler

-LSB-

-RSB-

defined

four

major

histo-anatomic

variants

of

vascular

calcification

including

classic

atherosclerotic

-LRB-

fibrotic

-RRB-

calcification

related

to

disorders

of

lipid

metabolism

medial

arterial

calcification

vascular

calcifilaxis

and

cardiac

valve

calcification

Spectrum

of

cardiovascular

abnormalities

in

children

with

CKD

Over

the

last

decade

abnormalities

of

the

LV

such

as

LVH

and

LV

dysfunction

abnormalities

of

the

large

arteries

such

as

stiffness

and

increased

intima-medial

thickness

-LRB-

IMT

-RRB-

of

the

carotids

and

calcification

of

the

coronaries

have

been

accepted

as

early

markers

of

cardiomyopathy

and

atherosclerosis

They

constitute

strong

independent

predictors

of

cardiac

morbidity

and

mortality

both

in

the

general

population

and

in

adults

with

CKD

In

children

and

young

adults

with

CKD

recent

studies

have

proven

that

these

abnormalities

are

also

present

and

that

risk

factors

for

cardiac

and

vascular

injury

in

children

with

CKD

are

similar

to

those

for

adults

Left

ventricular

hypertrophy

LVH

develops

when

renal

insufficiency

is

mild

or

moderate

in

children

and

progresses

as

renal

function

deteriorates

About

one

third

of

children

with

mild

to

moderate

renal

insufficiency

have

an

increased

left

ventricular

mass

-LRB-

LVM

-RRB-

index

-LSB-

-RSB-

In

a

prospective

longitudinal

study

of

pediatric

subjects

with

CKD

stage

Mitsnefes

et

al.

-LSB-

-RSB-

showed

that

a

substantial

proportion

of

children

had

a

significant

increase

in

the

LVM

index

with

many

of

the

children

developing

LVH

Indeed

of

the

patients

who

initially

had

a

normal

LVM

index

have

developed

incident

LVH

At

initiation

of

maintenance

dialysis

of

pediatric

patients

have

evidence

of

LVH

-LSB-

-RSB-

LVH

persists

-LRB-

-RRB-

during

long-term

dialysis

-LSB-

-RSB-

with

both

concentric

and

eccentric

geometric

patterns

of

LVH

present

in

these

patients

Post-mortem

studies

confirmed

high

rate

-LRB-

more

than

-RRB-

of

LVH

in

children

with

ESRD

-LSB-

-RSB-

Small

retrospective

studies

also

suggest

that

with

a

better

BP

and

volume

control

LVH

regression

might

be

achieved

in

young

patients

on

dialysis

-LSB-

-RSB-

On

the

other

hand

a

recent

retrospective

study

demonstrated

that

LVH

remains

very

prevalent

and

severe

in

a

selected

group

of

children

who

remained

on

maintenance

dialysis

for

at

least

years

-LSB-

-RSB-

As

in

children

prior

to

transplantation

most

pediatric

studies

indicate

that

LVH

remains

common

post

transplant

-LRB-

-RRB-

-LSB-

-RSB-

In

contrast

a

significantly

lower

frequency

of

LVH

was

found

in

a

study

by

Englund

et

al.

-LSB-

-RSB-

who

reported

the

results

of

a

longitudinal

analysis

of

children

receiving

renal

transplants

years

ago

Of

children

who

received

a

renal

transplant

between

and

survived

and

were

observed

for

to

years

At

the

follow-up

echocardiography

showed

minor

LVH

in

only

two

children

with

hypertension

No

child

without

hypertension

at

years

post

transplant

had

LVH

The

factors

associated

with

cardiac

hypertrophy

in

children

are

similar

to

those

in

adults

with

CKD

As

in

adults

most

pediatric

studies

of

patients

with

pre-terminal

terminal

renal

failure

and

post

transplant

found

significant

relationships

between

low

hemoglobin

and

an

increased

LVM

index

-LSB-

-RSB-

However

recent

adult

studies

in

mild

to

moderate

CKD

or

in

chronic

dialysis

determined

that

correction

of

anemia

was

not

associated

with

regression

of

LVH

-LSB-

-RSB-

Authors

suggested

that

relationships

between

anemia

and

LVH

might

not

be

causal

Of

note

the

above

studies

enrolled

subjects

with

relatively

mild

degrees

of

baseline

anemia

and

could

not

answer

the

question

whether

treatment

of

patients

with

initially

significantly

decreased

hemoglobin

levels

might

lead

to

a

reduction

of

LVM

In

contrast

Morris

et

al.

-LSB-

-RSB-

observed

a

significant

reduction

in

the

LVM

index

with

the

correction

of

severe

anemia

in

seven

children

on

chronic

dialysis

There

are

several

studies

on

the

association

between

parathyroid

hormone

-LRB-

PTH

-RRB-

levels

and

LVH

in

adults

with

CKD

-LSB-

-RSB-

In

children

elevated

PTH

is

associated

with

progression

of

LVH

in

stages

CKD

-LSB-

-RSB-

The

possible

mechanisms

of

parathyroid-induced

cardiac

hypertrophy

in

CKD

include

a

direct

effect

of

PTH

on

cardiomyocytes

and

an

indirect

effect

via

elevated

BP

-LSB-

-RSB-

A

support

for

a

causal

relationship

comes

from

in

vitro

studies

showing

that

PTH

appears

to

have

chronotropic

inotropic

as

well

as

hypertrophic

effects

on

cardiomyocytes

-LSB-

-RSB-

In

adults

with

CKD

hypertension

is

directly

linked

to

the

development

of

LVH

-LSB-

-RSB-

The

relationships

between

BP

and

LVH

in

pediatric

CKD

are

unclear

Consistent

correlations

of

LVM

and

BP

are

limited

to

children

with

ESRD

-LSB-

-RSB-

However

a

detailed

cross-sectional

analysis

of

BP

characteristics

by

ambulatory

blood

pressure

monitoring

-LRB-

ABPM

-RRB-

in

children

from

the

ESCAPE

trial

did

not

demonstrate

any

relationship

between

office

BP

or

ABPM

parameters

and

LVM

suggesting

only

a

minor

role

of

hypertension

in

the

pathogenesis

of

LVH

in

early

CRI

-LSB-

-RSB-

In

contrast

analysis

of

longitudinal

data

suggests

that

ABPM

might

be

an

important

tool

to

assess

the

risk

of

development

of

LVH

in

children

with

CKD

-LSB-

-RSB-

In

this

study

authors

determined

that

an

increase

in

the

nighttime

systolic

BP

load

-LRB-

number

of

BP

measurements

above

the

percentile

BP

value

-RRB-

were

independently

associated

with

the

increase

in

the

LVM

index

over

time

arguing

that

persistent

and

chronic

elevation

of

BP

might

be

more

important

in

the

development

of

LVH

-LSB-

-RSB-

Left

ventricular

function

In

contrast

to

adults

in

whom

systolic

dysfunction

is

frequently

associated

with

early

cardiac

failure

and

decreased

survival

in

children

with

CKD

systolic

LV

function

is

usually

preserved

-LSB-

-RSB-

On

the

other

hand

diastolic

dysfunction

often

the

initial

abnormality

of

cardiac

function

is

already

present

in

children

with

CKD

Doppler

measurement

of

mitral

inflow

velocity

has

been

the

most

widely

used

method

to

assess

LV

diastolic

function

Using

this

method

Goren

et

al.

-LSB-

-RSB-

showed

that

LV

relaxation

-LRB-

E/A

ratio

-RRB-

was

impaired

in

dialyzed

children

as

compared

to

controls

Johnstone

et

al.

-LSB-

-RSB-

also

found

a

reduction

in

the

E/A

ratio

in

children

on

chronic

peritoneal

dialysis

and

with

pre-terminal

renal

failure

although

of

these

patients

had

an

E/A

ratio

which

is

considered

to

be

abnormal

Unfortunately

the

transmitral

Doppler

velocities

and

therefore

the

E/A

ratio

are

affected

by

several

factors

including

left

atrial

pressure

and

preload

This

is

particularly

important

for

patients

with

advanced

chronic

renal

failure

since

many

of

them

are

hypervolemic

Recently

new

indices

were

introduced

to

evaluate

diastolic

function

using

tissue

Doppler

imaging

-LRB-

TDI

-RRB-

In

contrast

to

E/A

the

TDI

indices

may

be

less

load

dependent

and

provide

a

more

accurate

measure

of

diastolic

function

Recent

studies

employing

TDI

determined

that

children

with

CKD

might

have

abnormal

diastolic

function

-LSB-

-RSB-

In

these

studies

children

on

chronic

dialysis

had

significantly

worse

diastolic

dysfunction

than

children

with

mild-to-moderate

CRI

or

post

transplant

Poor

diastolic

function

in

patients

on

dialysis

was

associated

with

anemia

hyperphosphatemia

increased

calcium-phosphorus

ion

product

and

LVH

The

clinical

significance

of

diastolic

dysfunction

in

pediatric

patients

with

CKD

is

not

known

Longitudinal

studies

are

necessary

to

determine

if

abnormal

diastolic

function

predicts

the

development

of

systolic

dysfunction

and

congestive

heart

failure

in

these

patients

Arterial

structure

and

compliance

Studies

of

young

adults

who

developed

ESRD

during

childhood

found

a

high

prevalence

of

abnormal

carotid

IMT

diminished

arterial

wall

compliance

and

coronary

artery

calcification

-LRB-

CAC

-RRB-

These

vascular

abnormalities

are

accepted

as

markers

of

asymptomatic

atherosclerosis

and

predictors

of

future

symptomatic

CVD

in

the

general

population

and

in

adults

with

CKD

-LSB-

-RSB-

Groothoff

et

al.

-LSB-

-RSB-

found

increased

arterial

stiffness

and

showed

that

systolic

hypertension

was

the

main

determinant

of

abnormal

arterial

wall

compliance

Goodman

et

al.

-LSB-

-RSB-

showed

that

among

patients

on

chronic

dialysis

who

were

younger

than

years

of

age

had

evidence

of

CAC

in

contrast

of

the

patients

who

were

to

years

of

age

had

evidence

of

CAC

on

CT

scanning

Oh

et

al.

-LSB-

-RSB-

screened

for

coronary

and

carotid

artery

disease

in

patients

aged

to

years

with

childhood

onset

ESRD

Coronary

artery

calcification

was

present

in

and

carotid

IMT

was

significantly

increased

compared

to

matched

controls

Carotid

IMT

was

correlated

with

cumulative

dialysis

and

serum

Ca

x

P

product

in

their

study

Milliner

et

al.

-LSB-

-RSB-

in

an

autopsy

study

of

pediatric

patients

with

ESRD

who

died

in

showed

a

high

prevalence

of

soft

tissue

and

vascular

calcinosis

In

their

study

CAC

was

present

in

Peak

Ca

x

P

product

peak

serum

P

and

cumulative

dose

of

calcitriol

were

significantly

associated

with

the

severity

of

the

calcinosis

Civilibal

et

al.

-LSB-

-RSB-

screened

children

with

ESRD

for

the

presence

and

predisposing

factors

of

CAC

Coronary

artery

calcification

was

present

in

of

patients

-LRB-

three

hemodialysis

patients

three

peritoneal

dialysis

patients

and

two

renal

transplant

recipients

-RRB-

The

patients

with

CAC

had

a

longer

duration

of

total

dialysis

had

higher

time-integrated

serum

phosphorus

calcium-phosphate

product

intact

parathyroid

hormone

vitamin

levels

and

the

amount

of

cumulative

calcium-containing

oral

phosphate

binders

In

a

study

by

Briese

et

al.

-LSB-

-RSB-

of

young

adults

-LRB-

mean

age

years

-RRB-

who

developed

ESRD

at

a

mean

age

of

years

carotid

artery

IMT

was

similar

to

healthy

controls

and

only

-LRB-

-RRB-

patients

had

evidence

of

coronary

calcification

Authors

noticed

that

a

relatively

low

rate

of

cardiac

calcification

compared

to

other

studies

might

be

explained

by

a

significantly

lower

amount

of

prescribed

calcium-containing

phosphate

binders

and

vitamin

D

preparations

in

their

patients

Of

note

these

patients

had

decreased

vascular

reactivity

and

a

high

rate

of

LVH

-LRB-

-RRB-

As

in

adults

cardiac

valve

calcification

was

also

described

in

children

on

maintenance

dialysis

-LSB-

-RSB-

Evidence

of

early

atherosclerotic

changes

was

found

in

the

study

by

Nayir

et

al.

-LSB-

-RSB-

who

reported

on

the

histopathology

of

internal

iliac

artery

samples

obtained

at

the

time

of

kidney

transplantation

in

children

Five

arteries

had

fibrous

or

fibroelastic

intimal

thickening

medial

mucoid

ground

substance

and

disruption

of

the

internal

elastic

lamella

Two

of

these

had

microcalcification

in

the

intimal

layer

another

two

demonstrated

atheromatous

plaques

These

abnormalities

were

associated

with

longer

duration

of

renal

failure

Vascular

abnormalities

in

children

develop

in

parallel

with

cardiac

abnormalities

early

in

the

course

of

CKD

and

become

more

severe

as

end-stage

disease

is

reached

-LSB-

-RSB-

Mitsnefes

et

al.

-LSB-

-RSB-

showed

that

carotid

arteriopathy

is

present

in

children

after

successful

renal

transplantation

and

is

associated

with

hypertension

Litwin

et

al.

-LSB-

-RSB-

as

a

part

of

the

ESCAPE

trial

investigated

vascular

structure

and

function

in

children

with

chronic

renal

failure

and

after

renal

transplantation

The

authors

demonstrated

vascular

abnormalities

in

all

patient

groups

with

the

most

marked

changes

in

the

dialysis

patients

The

degree

of

arteriopathy

in

their

study

was

correlated

with

conventional

CVD

risk

factors

such

as

hypertension

and

dyslipidemia

in

pre-dialytic

CKD

while

in

children

on

dialysis

and

after

transplantation

hyperphosphatemia

hyperparathyroidism

and

treatment

with

calcium-containing

phosphate

binders

were

determinants

of

arterial

abnormalities

Another

important

observation

in

this

study

was

a

significantly

lower

carotid

IMT

in

children

post

transplant

suggesting

that

the

vascular

abnormalities

partially

regress

Epidemiological

studies

should

determine

if

vascular

abnormalities

detected

during

childhood

CKD

are

associated

with

future

accelerated

coronary

artery

disease

Endothelial

dysfunction

as

a

marker

of

early

atherosclerosis

in

children

with

CKD

Endothelial

function

can

be

evaluated

by

the

assessing

of

endothelial

vasodilatation

Healthy

vascular

endothelium

will

respond

to

the

release

of

nitric

oxide

by

vasodilatation

With

endothelial

injury

the

response

to

nitric

oxide

is

diminished

-LSB-

-RSB-

and

endothelial-mediated

vasodilatation

is

impaired

Flow-mediated

dilation

-LRB-

FMD

-RRB-

of

the

brachial

artery

is

currently

used

to

measure

endothelial

function

This

test

consists

of

applying

obstruction

to

the

flow

of

the

brachial

artery

by

placing

the

tourniquet

or

inflated

BP

cuff

for

few

minutes

The

artery

dilates

due

to

post-obstruction

reactive

hyperemia

FMD

is

calculated

based

on

the

difference

in

the

diameter

of

the

brachial

artery

before

obstruction

and

after

it

released

Impaired

-LRB-

decreased

-RRB-

FMD

predicts

CVD

morbidity

and

mortality

in

adults

with

ESRD

-LSB-

-RSB-

It

has

been

shown

that

endothelial

dysfunction

as

determined

by

impaired

FMD

is

also

present

in

children

with

advanced

renal

failure

on

chronic

dialysis

and

after

renal

transplantation

-LSB-

-RSB-

Evaluation

and

treatment

recommendations

The

overall

strategy

in

the

prevention

of

cardiovascular

complications

in

children

with

CKD

is

avoidance

of

long-term

dialysis

The

goal

is

to

prevent

the

development

and

delay

the

progression

of

cardiomyopathy

and

atherosclerosis

The

identification

of

modifiable

risk

factors

and

markers

of

CVD

and

early

intervention

should

be

initiated

at

the

time

of

mild-to-moderate

renal

insufficiency

prior

to

the

need

for

dialysis

Even

though

kidney

transplantation

poses

a

continuous

CV

risk

-LRB-

hypertension

hyperlipidemia

and

allograft

dysfunction

-RRB-

it

eliminates

many

uremia-related

risks

reduces

the

risk

of

cardiac

death

by

approximately

percent

and

prolongs

the

life

span

by

years

Thus

kidney

transplantation

should

be

the

ultimate

goal

to

minimize

cardiovascular

morbidity

and

mortality

in

patients

with

advanced

CKD

For

those

patients

who

must

have

long-term

dialysis

the

strategy

is

directly

linked

to

achievement

of

optimal

dialysis

outcomes

which

include

aggressive

monitoring

and

management

of

hypertension

dyslipidemia

calcium-phosphorus

metabolism

anemia

nutrition

systemic

inflammation

and

other

dialysis

complications

Current

recommendations

on

evaluation

of

CV

abnormalities

and

treatment

of

modifiable

risk

factors

in

children

are

based

mostly

on

clinical

experience

and

adult

data

Recent

K/DOQI

Clinical

Practice

Guidelines

for

Cardiovascular

Disease

in

Dialysis

Patients

-LSB-

-RSB-

recommend

echocardiographic

evaluation

for

the

presence

of

cardiac

disease

in

children

-LRB-

cardiomyopathy

and

valvular

disease

-RRB-

at

the

time

of

initiation

of

dialysis

therapy

along

with

the

screening

for

dyslipidemia

hypertension

anemia

and

increased

Ca

P

product

Management

of

modifiable

risks

in

children

with

CKD

should

follow

recommendations

from

the

K/DOQI

guidelines

for

treatment

of

anemia

-LSB-

-RSB-

and

dyslipidemia

-LSB-

-RSB-

and

from

the

Fourth

Report

on

Blood

Pressure

in

Children

for

Management

of

Hypertension

-LSB-

-RSB-

Current

K/DOQI

guidelines

for

treatment

of

anemia

recommend

keeping

the

hemoglobin

level

above

g/dl

by

using

an

appropriate

iron

therapy

and

recombinant

erythropoietin

In

the

opinion

of

the

Working

Group

there

is

insufficient

evidence

to

recommend

routinely

maintaining

hemoglobin

levels

above

g/dl

or

more

K/DOQI

recommends

evaluation

of

dyslipidemia

in

adolescents

upon

presentation

with

CKD

stage

-LRB-

GFR

or

on

dialysis

-RRB-

at

months

after

a

change

in

treatment

or

other

conditions

known

to

cause

dyslipidemia

and

at

least

annually

thereafter

Reasons

to

repeat

lipid

measurements

after

months

include

changes

in

the

kidney

replacement

therapy

modality

treatment

with

diet

or

lipid-lowering

agents

immunosuppressive

agents

that

affect

lipids

-LRB-

e.g.

prednisone

cyclosporine

or

sirolimus

-RRB-

or

other

changes

that

may

affect

plasma

lipids

The

assessment

of

dyslipidemia

should

include

a

complete

fasting

lipid

profile

with

total

cholesterol

LDL

HDL

and

triglycerides

The

definition

of

dyslipidemia

differs

in

children

and

adults

Hyperlipidemia

in

children

is

defined

as

lipid

levels

greater

than

the

percentile

for

age

and

gender

The

normative

data

for

lipids

in

children

and

adolescents

currently

used

are

from

the

Lipid

Research

Clinics

Program

from

the

NIH

published

in

and

can

be

found

in

the

K/DOQI

guidelines

for

management

of

dyslipidemia

in

chronic

kidney

disease

-LSB-

-RSB-

For

adolescents

with

stage

CKD

and

a

level

of

LDL

mg/dl

K/DOQI

recommends

treatment

to

reduce

LDL

to

mg/dl

If

LDL

is

mg/dl

fasting

triglycerides

mg/dl

and

non-HDL

cholesterol

-LRB-

total

cholesterol

minus

HDL

-RRB-

mg/dl

treatment

should

be

considered

to

reduce

non-HDL

cholesterol

to

mg/dl

All

children

with

dyslipidemia

should

follow

the

recommendations

for

therapeutic

lifestyle

changes

-LRB-

TLC

-RRB-

which

include

diet

modification

with

a

reduction

in

saturated

fat

intake

and

increase

in

fiber

intake

and

moderate

physical

activity

Adolescents

should

be

counseled

about

avoiding

smoking

Unfortunately

non-compliance

with

TLC

is

one

of

the

major

problems

in

the

management

of

dyslipidemia

in

adolescents

Pediatric

nephrologists

must

also

recognize

that

appropriate

caloric

intake

including

calories

from

fat

should

be

emphasized

to

avoid

malnutrition

and

ensure

normal

growth

and

development

especially

in

young

children

If

LDL

cholesterol

is

mg/dl

and

non-HDL

cholesterol

mg/dl

statin

therapy

is

recommended

in

children

older

than

years

Target

blood

pressure

in

children

should

be

lower

than

the

percentile

for

normal

values

adjusted

for

age

gender

and

height

or

less

than

mm

Hg

whichever

is

lower

Ambulatory

blood

pressure

monitoring

is

recommended

to

assess

the

circadian

rhythm

Angiotensin-converting

enzyme

inhibitors

or

angiotensin

receptor

blockers

may

be

the

preferred

antihypertensive

agents

to

slow

the

progression

of

CKD

in

children

and

possibly

for

regression

of

LVH

The

Working

Group

on

Cardiovascular

Disease

in

Dialysis

Patients

recommends

maintaining

calcium

and

phosphorus

levels

within

the

normal

range

and

the

Ca

P

product

in

children

on

chronic

dialysis

-LSB-

-RSB-

There

are

no

data

available

to

make

evidence-based

recommendations

on

management

of

hyperhomocysteinemia

chronic

inflammation

or

other

potential

CVD

risk

factors

Questions

-LRB-

Answers

appear

following

the

references

-RRB-

A

African-American

boy

with

ESRD

secondary

to

FSGS

has

been

treated

with

thrice-weekly

hemodialysis

for

year

His

pre-dialysis

BP

is

hemoglobin

is

g/dl

serum

calcium

is

g/dl

serum

phosphorus

is

g/dl

and

iPTH

is

pg/ml

He

is

taking

a

calcium

channel

blocker

to

control

his

hypertension

erythropoietin

and

iron

to

control

his

anemia

and

calcium

carbonate

and

a

vitamin

D

IV

preparation

to

control

his

renal

bone

disease.Which

ONE

of

the

following

statements

would

be

the

BEST

therapeutic

intervention

in

this

child

to

minimize

the

risk

of

future

CV

complications?Aggressive

treatment

of

hypertensionMaximize

dialysis

treatment

to

achieve

dry

weightCorrection

of

anemiaKidney

transplantationReduction

of

Ca-P

productThe

patient

from

the

previous

question

was

diagnosed

with

eccentric

LVH.With

regard

to

treatment

of

his

LVH

which

ONE

of

the

following

actions

is

MOST

LIKELY

to

lead

to

reduction

of

LVH?Adding

ACE

inhibitor

as

a

second

antihypertensive

agentIncrease

the

dose

of

erythropoietin

and

assure

appropriate

iron

status

to

treat

anemiaAchievement

of

dry

weightSwitch

from

hemodialysis

to

peritoneal

dialysisMaximize

treatment

of

secondary

hyperparathyroidismThe

annual

evaluation

showed

that

this

patient

has

LDL

cholesterol

of

mg/dl

You

would

like

to

start

this

patient

on

atorvastatin.With

regard

to

the

use

of

statin

in

this

patient

which

ONE

of

the

following

statements

is

correct?Statins

are

not

approved

by

the

United

States

Food

and

Drug

Administration

-LRB-

USFDA

-RRB-

for

use

in

children

and

adolescentsGrapefruit

is

contraindicatedThe

dose

of

atorvastatin

should

be

reduced

by

compared

to

dosage

in

adult

patients

on

dialysis

to

prevent

adverse

effects

on

growth

and

developmentThe

target

level

for

LDL

cholesterol

in

children

with

CKD

should

be

below

mg/dlAtorvastatin

therapy

will

reduce

mortality

risk

in

this

patientWhich

ONE

of

the

following

statements

concerning

development

of

cardiovascular

complications

in

a

child

with

CKD

is

NOT

correct?Cardiovascular

disease

is

the

cause

of

mortality

in

approximately

of

chronically

dialyzed

childrenCardiac

arrest

is

the

most

common

cardiac

cause

of

death

in

children

with

ESRDCardiac

and

vascular

remodeling

might

develop

in

children

during

early

stages

of

CKDCorrection

of

anemia

reduces

concentric

LVHLVH

is

the

most

common

cardiac

abnormality

in

children

on

maintenance

dialysisThe

patient

described

in

the

previous

questions

is

at

risk

for

development

of

vascular

calcification.Which

ONE

of

the

following

choices

does

NOT

correctly

describe

the

mechanisms

of

vascular

calcification

in

dialyzed

patients?Histo

anatomic

variants

of

calcification

include

classic

atherosclerotic

-LRB-

fibrotic

-RRB-

calcification

related

to

disorders

of

lipid

metabolism

medial

arterial

calcification

vascular

calcifilaxis

and

cardiac

valve

calcificationIncreased

Ca-P

product

and

hyperphosphatemia

are

the

key

drivers

of

vascular

calcification

in

young

patients

with

CKDInflammatory

mechanisms

are

involved

in

mediating

all

stages

of

atherosclerosis

including

calcificationIncreased

serum

level

of

Fetuin-A

promotes

Ca-P

ion

product

-LRB-

OH

-RRB-

increases

calcium

deposition

in

the

vascular

wall

Answers

dcbdd

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

chronic kidney disease
children
cardiovascular disease
esrd


Loss of treatment benefit due to low compliance with bisphosphonate therapy Summary Among 8,822 new female bisphosphonate users , non-compliant bisphosphonate use was associated with a 45 % increased risk of osteoporotic fracture compared to compliant use -LRB- MPR ≥ 80 % -RRB- . Classifying compliance into five categories , fracture risk gradually increased with poorer compliance . These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit . Introduction Osteoporosis is a systemic condition characterized by low bone mass and microarchitectural deterioration of bone tissue , leading to enhanced bone fragility and , consequently , an increased fracture risk -LSB- 1 -RSB- . Osteoporosis has clinical and public health importance because osteoporotic fractures are one of the most common causes of disability and a major contributor to medical costs in many regions of the world -LSB- 2 -RSB- . Bisphosphonates are potent inhibitors of the osteoclast-mediated resorption of bone and widely used to treat osteoporosis and reduce the risk of osteoporotic fractures -LSB- 3 -RSB- . Long-term therapy with bisphosphonates is required to realise the full benefits of this treatment -LSB- 3 , 4 -RSB- . This is supported by a recent PHARMO study that showed that the risk of fractures was reduced by 26 % after one year persistent bisphosphonate use and up to 32 % after two year persistent use -LSB- 5 -RSB- . However , in daily clinical practice , 50 % to 75 % of patients discontinue bisphosphonate use already in the first year of therapy -LSB- 5 -- 8 -RSB- . Moreover , non-compliance with bisphosphonates has also been reported to be a frequent issue , with rates varying from 35 % to 65 % -LSB- 6 , 9 -RSB- . Reasons for low compliance with bisphosphonate treatment are the stringent regimen to minimize the risk of oesophageal irritation , the existence of drug-related gastrointestinal side effects , and the fact that osteoporosis is often asymptomatic in early stages -LSB- 10 -RSB- . Caro et al. showed that patients who were compliant with their osteoporosis medication , including bisphosphonates , estrogens and calcitonin , experienced a 16 % lower fracture rate compared to non-compliant users -LSB- 11 -RSB- . The objective of this study was to investigate the risk of osteoporotic fractures associated with low compliance with bisphosphonates in more detail . In addition to dichotomizing compliance , we also classified compliance into five categories . Patients and methods Setting Data were obtained from the PHARMO Record Linkage System -LRB- PHARMO RLS -RRB- which includes several databases , among which drug dispensing and hospitalization data of more than two million residents of the Netherlands . The drug dispensing histories contain data on the dispensed drug , the type of prescriber , the dispensing date , the amount dispensed , the prescribed dose regimens , and the duration of use . All drugs are coded according to the Anatomical Therapeutic Chemical -LRB- ATC -RRB- Classification . The hospital records include detailed information concerning the primary and secondary diagnoses , procedures , and dates of hospital admission and discharge . All diagnoses are coded according to the International Classification of Diseases , 9th Revision , Clinical Modification -LRB- ICD-9-CM -RRB- . Study cohort The source population included all new users of bisphosphonates in the period from January 1999 until July 2004 . These patients were not dispensed any anti-osteoporotic drugs -LRB- bisphosphonates , raloxifene , tibolone , estrogens , hormone replacement therapy , calcitonin or teriparatide -RRB- for at least one year before their first bisphosphonate dispensing . All female new users of alendronate -LRB- 10 mg daily or 70 mg weekly -RRB- or risedronate -LRB- 5 mg daily or 35 mg weekly -RRB- -LRB- i.e. the dosages indicated for the prevention or treatment of postmenopausal osteoporosis -RRB- , aged ≥ 45 years or with diagnosed postmenopausal osteoporosis -LRB- ICD-9-CM code 733.01 -RRB- , without gaps in registration in PHARMO RLS , and with a registration of at least one year before and one year after starting bisphosphonate treatment were included in the study cohort . All study patients were followed from the first bisphosphonate dispensing until the occurrence of the outcome of interest , death , end of registration in PHARMO RLS or end of the study period , whichever event was earliest . Compliance Compliance with bisphosphonates during follow-up may change and was measured over 90-day intervals using the Medication Possession Ratio -LRB- MPR -RRB- . MPR was defined as the sum of days ' supply of all alendronate and risedronate dispensings during or overlapping the 90-day interval divided by 90 potential days of bisphosphonate therapy . For each dispensing only the days ' supply covering a specific interval were counted . E.g. of a 100-days supply dispensed at follow-up day 60 , only 30 days were counted when calculating the MPR over the first interval -LRB- day 0 -- 90 -RRB- and 70 days for the MPR over the second interval -LRB- day 91 -- 180 -RRB- . The maximum value of a MPR was set at 1 . Subdividing follow-up in larger intervals was assumed too rough and subdividing in smaller intervals was not feasible regarding the usual prescription length of 90 days . Osteoporotic fractures The outcome variable osteoporotic fracture was defined as hospitalisation for an osteoporotic fracture during follow-up . Hospitalisations were selected based on primary discharge diagnosis for probable -LRB- ICD-9-CM codes 805.2 -LRB- vertebral thoracic -RRB- , 805.4 -LRB- vertebral lumbar -RRB- , 820 -LRB- proximal femur -RRB- , 812 -LRB- proximal humerus -RRB- , 813.4 -LRB- distal radius/ulna -RRB- , 814 -LRB- carpus -RRB- -RRB- or possible -LRB- ICD-9-CM codes 823.0 -LRB- proximal tibia/fibula -RRB- , 807.0 -LRB- rib -RRB- , 807.2 -LRB- sternum -RRB- , 808.0 -LRB- pelvis -RRB- -RRB- osteoporotic fractures . Covariates For all patients , a history of osteoporotic fracture was assessed . Furthermore , we determined use of non-steroidal anti-inflammatory drugs , analgesics , benzodiazepines and antidepressants in the year after starting bisphosphonate treatment as these drugs are associated with an increased risk of fractures -LSB- 12 -- 14 -RSB- . Similarly , we assessed use of thiazide diuretics , ß-blockers and statins in the year after start as these drugs are associated with a reduced risk of fractures -LSB- 15 -- 17 -RSB- . Statistical analyses The association between low compliance with bisphosphonates and the risk of fractures was analysed univariately and multivariately using time-dependent Cox regression analysis to account for changing compliance over time . In this analysis , at the time of each fracture , the cumulative compliance up to and including the corresponding 90-day interval of women who had experienced a fracture was compared to the cumulative compliance of those women who remained fracture-free at this time . The cumulative compliance of the fracture-free patients was measured up to the interval of corresponding fracture . In a first analysis , compliance was dichotomized and a MPR < 80 % , i.e. non-compliant bisphosphonate use was compared to a MPR ≥ 80 % , i.e. compliant use . In a second analysis , compliance was classified into five categories : < 20 % , 20 -- 49 % , 50 -- 69 % , 70 -- 89 % and ≥ 90 % -LRB- reference -RRB- . A Wald test for trend was performed . Assuming that the effect of bisphosphonates is not immediate , and in line with Caro et al. -LSB- 11 -RSB- , fractures occurring in the first 182 days of follow-up were excluded from the analyses . In a sub-analysis , this exclusion period was varied . Furthermore , an additional analysis was performed excluding women with only one bisphoshonate dispensing during follow-up ; in these patients it is less sure that they actually used the drug . The multiple regression models included age , history of fracture and all covariates that were univariately associated with the risk of fractures and significantly contributed to the multivariate model , i.e. inclusion of the covariate resulted in a change of the compliance hazard ratio -LRB- HR -RRB- of 5 % or over , starting with the most potent covariate . HRs and 95 % confidence intervals -LRB- CI -RRB- were estimated using SAS V8 .2 UNIX -LRB- Cary , NC , USA -RRB- . Results The study cohort included 8,822 new female users of daily or weekly alendronate or risedronate , who contributed a total of 22,484 person-years of follow-up during the study period . More than half of the patients were older than 70 years of age -LRB- n = 4,708 , 53 % -RRB- and about one quarter of the patients used corticosteroids -LRB- irrespective of quantity -RRB- -LRB- Table 1 -RRB- . The first bisphosphonate was mainly prescribed by the general practitioner -LRB- 64 % -RRB- . Only 197 patients -LRB- 2 % -RRB- were hospitalized for an osteoporotic fracture in the year before starting treatment . Table 1General characteristics of new bisphosphonate users between 1 January 1999 and 30 June 2004 -LRB- N = 8,822 -RRB- CharacteristicN % Age class -LRB- years -RRB- 45 -- 5488910.155 -- 693,22536.5 ≥ 704,70853.4 Mean age -LRB- years -RRB- ± sd 69.4 ± 10.3 Year of start1999 / 20002,25025.52001 / 20022,76931.42003 / 20043,80343.1 Initial bisphosphonateDaily bisphosphonate4 ,22247.9 Weekly bisphosphonate4 ,60052.1 First prescriberGeneral practitioner5 ,70464.7 Internist , rheumatologist , orthopedist2 ,31326.2 Other prescribers8059 .1 Hospitalization for an osteoporotic fracture in the year before start 1972.2 Use of corticosteroids in the year before start -LRB- irrespective of quantity -RRB- 2,38927.1Follow-up time -LRB- months -RRB- 12 -- 232,93933.324 -- 352,26825.7 ≥ 363,61541.0 During follow-up , 216 patients -LRB- 2 % -RRB- experienced an osteoporotic fracture , of which 40 patients during the first six months and 78 during the first year . About two third of all osteoporotic fractures were located at the proximal femur . The percentage of patients with a MPR < 80 % -LRB- i.e. non-compliant patients -RRB- increased from 34 % -LRB- 3,018 / 8,822 -RRB- after six months of follow-up to 42 % -LRB- 3,743 / 8,822 -RRB- after one year , 51 % -LRB- 3,014 / 5,883 -RRB- after two years and 60 % -LRB- 2,149 / 3,615 -RRB- after three years of follow-up . Subdividing MPR in classes -LRB- Fig. 1 -RRB- , the majority of patients either had a MPR ≥ 90 % or a MPR < 20 % , with the first group decreasing and the latter group increasing over time . Fig. 1Compliance with bisphosphonates , classified in five MPR categories , after six months , one year , two years and three years of follow-up . MPR : medication possession ratio Dichotomizing compliance , a MPR < 80 % , i.e. non-compliant bisphosphonate use was associated with a 40 % increased risk of osteoporotic fracture more than six months after starting treatment -LRB- HR 1.41 95 % CI 1.04 -- 1.91 , adjusted for age and history of fracture -LRB- see Table 2 for association between co-variates and fracture risk -RRB- -RRB- compared to a MPR ≥ 80 % , i.e. compliant use . Varying the exclusion period , i.e. excluding fractures occurring in the first year of follow-up or including all fractures during follow-up , yielded similar adjusted increased risks -LRB- HR 1.50 ; 95 % CI 1.06 -- 2.13 and HR 1.45 ; 95 % CI 1.10 -- 1.91 , respectively -RRB- . Excluding women who received only one bisphosphonate dispensing during follow-up also did not change the results -LRB- adjusted HR 1.45 ; 95 % CI 1.05 -- 1.99 , based on 156 fracture patients and 7,758 fracture-free patients -RRB- . Table 2Association between co-variates and fracture risk more than six months after starting treatment Fracture patients -LRB- N -RRB- Fracture-free patients -LRB- N -RRB- N % N % HRcrude95 % CITotal1761008 ,606100 Age -LRB- years -RRB- at start 45 -- 5474.087910.21.00 reference 55 -- 692916.53,18937.11.160.51 -- 2.66 ≥ 7014079.54,53852.74.282.00 -- 9.15 Year of start 1999/20008648 .92,15825.11.681.04 -- 2.71 2001/20026335 .82,69131.31.550.97 -- 2.49 2003/20042715 .33,75743.61.00 referenceHistory of osteoporotic fracture52 .81902.21.520.63 -- 3.70 Comedication in the year after start1 Analgesics6838 .62,13624.81.821.34 -- 2.46 Benzodiazepines8045 .53,32438.61.300.96 -- 1.74 Antidepressants2916 .51,04612.21.521.02 -- 2.26 ß-blockers4726.71 ,92922.41.350.97 -- 1.89 HR : hazard ratio , CI : confidence interval1 Univariate non-significant comedications -LRB- i.e. non-steroidal anti-inflammatory drugs , thiazides and statins -RRB- are not shown . Classifying compliance into five categories , fracture risk gradually increased with poorer compliance -LRB- p-value < 0.05 for trend -RRB- . Compared to a MPR ≥ 90 % , the adjusted risk of fracture increased from 1.2 times for a MPR between 50 % and 90 % to 1.8 times for a MPR less than 20 % -LRB- Fig. 2 -RRB- . Fig. 2The relationship between compliance with bisphosphonates , classified in five MPR categories , and fracture risk more than half a year after starting treatment . HRs are adjusted for age and history of fracture and are compared to a MPR ≥ 90 % . MPR : medication possession ratio , HR : hazard ratio , CI : confidence interval Discussion This study indicates that non-compliant bisphosphonate users had an approximately 50 % higher likelihood of osteoporotic fracture compared to compliant users . Classifying compliance into five categories , fracture risk gradually increased with poorer compliance to an 80 % risk increase with very low compliance compared to very high compliance . These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit . To quantify the loss of treatment benefit with low compliance , information on fracture risk in women not treated with bisphosphonates is necessary . The above mentioned percentage risk increases are compared to compliant use and can not be translated into percentage loss of treatment benefit . We chose not to use untreated patients as reference because of the heterogeneity of patterns of treatment use that exist within this group . In a meta-analysis of 11 trials of alendronate for the treatment of postmenopausal osteoporosis , a consistent 50 % reduction in fracture risk was seen compared to placebo -LSB- 18 -RSB- . For risedronate , a meta-analysis of 8 trials revealed a 25 to 35 % reduction in fracture risk compared to placebo -LSB- 19 -RSB- . In other words , untreated women are 1.5 to 2 times as likely to experience a fracture compared to women using bisphosphonates . Assuming that the patients with a MPR ≥ 90 % in our study are comparable to the treated patients in trials , the 1.6 to 1.8 times increased fracture risk we observed with a MPR < 50 % can be translated into a 80 to 100 % loss of treatment benefit . Apparently , patients with the lowest compliance are essentially comparable to non-treated patients . At present , in addition to Caro et al. , others have reported on the relationship between compliance with bisphosphonates and fracture risk -LSB- 11 , 20 , 21 -RSB- . Siris et al. -LSB- 20 -RSB- found a relative fracture risk reduction of 25 % with compliant use of alendronate or risedronate , i.e. a 33 % risk increase with non-compliant use . There was a progressive relationship between compliance and fracture risk reduction , commencing at a MPR around 50 % and becoming more pronounced at a MPR ≥ 75 % . This finding , like our results , suggests that low-compliant patients gain only marginal benefit from bisphosphonate therapy . Among women starting drug therapy for osteoporosis -LRB- of which two-third bisphosphonates -RRB- Weycker et al. -LSB- 21 -RSB- found that compared to women with a MPR < 30 % , the odds of fracture was similar -LRB- 1.02 -RRB- for women with a MPR between 30 and 69 % and women with a MPR between 70 and 89 % , but lower -LRB- 0.70 -RRB- for women with a MPR ≥ 90 % . The latter corresponds to a 1.4 times increased risk of fracture with a MPR < 30 % compared to a MPR ≥ 90 % . Caro et al. -LSB- 11 -RSB- reported that compared to a MPR > 90 % , fracture risk was significantly increased at lower compliance levels , i.e. up to 1.4 times with a MPR ≤ 50 % . However , it is not clear whether this effect was gradual . In a study population of mainly users of hormone replacement therapy , Huybrechts et al. -LSB- 22 -RSB- found that compared to women with a MPR ≥ 90 % , fracture risk was similar -LRB- HR 1.09 -RRB- for women with a MPR between 80 and 90 % , but higher for women with a MPR between 50 and 80 % and women with a MPR < 50 % -LRB- HR 1.18 and 1.21 , respectively -RRB- . Our associations are about similar than reported by Siris et al. , but stronger than found by Caro et al. , Weycker et al. and Huybrechts et al. . The most likely explanation for this is that our and Siris ' study population was restricted to bisphosphonate users , while the others also included users of other , less potent anti-osteoporotic drugs -LRB- 30 % to 65 % of the study population -RRB- . There is a previous PHARMO study on bisphosphonate use and risk of fractures , using persistence -LSB- 5 -RSB- . Besides a different measure of drug exposure , the current study differs from this previous study in that the study period was extended , different inclusion criteria were applied and new patients were included besides previously studied patients . Although persistence and compliance are measured differently , with persistence referring to the duration of uninterrupted drug use , they are closely related . Patients classified as non-compliant would also have been classified as non-persistent and vice versa . The results of our current study are in line with our previous study in which the risk of fractures was reduced by 26 % after one year persistent bisphosphonate use and up to 32 % after two years of persistent use -LSB- 5 -RSB- . Similarly , Gold et al -LSB- 23 -RSB- reported that persistent bisphosphonate use for at least 6 months was associated with a 26 % lower fracture risk . Expressing these results the other way around , non-persistent bisphosphonate use is associated with an about 40 % fracture risk increase . Among a population of mainly users of hormone replacement therapy , one year of uninterrupted therapy reduced the likelihood of fractures with significant odds ratios of 0.38 for hip fractures and 0.60 for vertebral fractures -LSB- 7 -RSB- . Our analyses may be limited by some issues common to observational database research in daily clinical practice . Most importantly , although we considered a large number of known confounders in our analyses , including history of fractures , there may be other confounding factors for which information was not available , such as bone mineral density -LRB- BMD -RRB- . BMD is an important determinant of fracture risk -LSB- 24 -RSB- and BMD testing has been shown to be positively associated with persistence and compliance -LSB- 25 , 26 -RSB- . Consequently , the results of our analyses are likely to be conservative in the sense that compliant patients may have had an increased fracture risk because of low BMD , and history of fractures only partially controlled for this . Furthermore , it is possible that patients have started using other anti-osteoporotic drugs , e.g. raloxifene , during follow-up and stopped bisphosphonate use . This means that part of the patients who were non-compliant with bisphosphonates may have been protected against fractures by another anti-osteoporotic drug and the observed increased fracture risk with non-compliant bisphosphonate use therefore may be underestimated . However , we know from our database that this concerns only about 7 % of patients in the first year of bisphosphonate treatment . In addition , compliance with treatment was based on dispensing data . As it is unknown whether a patient actually used the drug , compliance may have been overestimated . However , it seems likely that patients who obtain prescription refills do take their medication . Excluding women who filled only one bisphosphonate dispensing during follow-up from the analyses did not change the results . Another limitation relates to the classified analysis . With the use of five compliance categories studying a trend is possible but it does not give information on the point at which there is a significant shift in fracture risk . Ideally , 10 % MPR categories should be used . However , patient numbers per 10 % MPR categories -LRB- data not shown -RRB- did not allow for this detailed analysis . To increase the treatment benefit of bisphosphonates , compliance should be improved . Related to the inconvenient , stringent intake regimen , dosing frequency is an important determinant of compliance with bisphosphonates . In recent earlier studies , once-weekly dosing was associated with better compliance and persistence compared to daily dosing . However , even with the weekly regimen , compliance and persistence were suboptimal in about half of the patients -LSB- 6 , 8 , 9 -RSB- . Bisphosphonates with less frequent dosing regimes than weekly , e.g. monthly or three-monthly ibandronate or annual zolendronate , are either available yet or upcoming and may further improve compliance and therefore treatment benefit . In a cross-over trial , women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy and found it more convenient than once-weekly alendronate therapy -LSB- 27 -RSB- . There are no data yet on the actual impact of this once-monthly , and other formulations on compliance with bisphosphonate therapy and reduction of fracture risk in daily practice . Other keys to improve compliance are e.g. healthcare provider - patient communication and continuous reinforcement of the importance of treatment . Reminder systems may help the patient comply with therapy , especially with infrequent dosing regimes . However , results from a review show that current methods of improving patient compliance for several chronic health problems are mostly not very successful -LSB- 28 -RSB- . Furthermore , although a number of demographic and clinical variables are associated with compliance with bisphosphonates these predictors , either individually or together , have been shown to have low predictive value for identifying patients who will become non-compliant -LSB- 25 -RSB- . In conclusion , the results of this study show a statistically significant association between level of compliance with bisphosphonates and level of fracture risk , emphasizing the importance of treatment compliance in obtaining maximal bone protection .

O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O

benefit bisphosphonates fracture osteoporosis