Pathophysiology

of

focal

segmental

glomerulosclerosis

Focal

segmental

glomerulosclerosis

-LRB-

FSGS

-RRB-

is

a

major

cause

of

idiopathic

steroid-resistant

nephrotic

syndrome

-LRB-

SRNS

-RRB-

and

end-stage

kidney

disease

-LRB-

ESKD

-RRB-

In

recent

years

animal

models

and

studies

of

familial

forms

of

nephrotic

syndrome

helped

elucidate

some

mechanisms

of

podocyte

injury

and

disease

progression

in

FSGS

This

article

reviews

some

of

the

experimental

and

clinical

data

on

the

pathophysiology

of

FSGS

Learning

objectives

Discuss

the

experimental

and

clinical

data

on

the

pathophysiology

of

FSGSReview

the

alterations

in

glomerular

structure

and

function

associated

with

FSGSTo

identify

potential

mechanisms

responsible

for

disease

progression

in

FSGSDistinguish

some

targets

for

the

future

therapy

of

FSGS

Focal

segmental

glomerulosclerosis

-LRB-

FSGS

-RRB-

is

a

disease

entity

defined

by

findings

on

kidney

biopsy

-LSB-

-RSB-

FSGS

is

the

major

cause

of

idiopathic

steroid-resistant

nephrotic

syndrome

-LRB-

SRNS

-RRB-

in

children

and

adults

-LSB-

-RSB-

FSGS

is

the

most

common

cause

of

acquired

chronic

renal

insufficiency

in

children

and

frequently

leads

to

progression

to

end-stage

kidney

disease

-LRB-

ESKD

-RRB-

-LSB-

-RSB-

FSGS

may

occur

secondary

to

such

disparate

disease

processes

as

HIV

and

obesity

-LSB-

-RSB-

this

review

focuses

on

the

pathophysiology

of

primary

FSGS

-LRB-

i.e.

with

no

underlying

illness

-RRB-

Alterations

of

normal

glomerular

structure

and

function

have

been

found

in

FSGS

-LSB-

-RSB-

Normal

function

requires

that

the

three

major

components

of

the

glomerular

filter

-LRB-

the

endothelial

cells

podocytes

and

glomerular

basement

membrane

-RRB-

are

intact

and

are

able

to

provide

a

permselective

filtration

barrier

-LRB-

Fig.

-RRB-

Specialized

tight

junctions

between

podocyte

foot

processes

create

the

slit

diaphragm

which

is

integral

to

preventing

the

loss

of

protein

into

the

urinary

space

-LSB-

-RSB-

While

the

clinical

presentation

of

FSGS

is

often

heterogeneous

a

characteristic

feature

of

the

disease

is

proteinuria

which

implies

the

loss

of

this

barrier

-LSB-

-RSB-

Indeed

electron

microscopy

has

shown

distortion

of

the

normal

architecture

-LRB-

or

effacement

-RRB-

of

the

foot

processes

of

podocytes

in

FSGS

-LSB-

-RSB-

The

connection

between

these

projections

of

the

epithelial

cell

and

the

underlying

basement

membrane

can

be

disrupted

leading

to

the

loss

of

nonspecific

plasma

proteins

into

the

tubular

filtrate

-LSB-

-RSB-

Fig.

Components

of

the

normal

glomerular

filtration

barrier

-LRB-

-RRB-

glomerular

basement

membrane

-LRB-

GBM

-RRB-

-LRB-

-RRB-

podocyte

foot

process

-LRB-

-RRB-

endothelial

cell

B

Progressive

changes

seen

in

focal

segmental

glomerulosclerosis

-LRB-

FSGS

-RRB-

leading

to

sclerosis

-LRB-

-RRB-

foot

process

effacement

-LRB-

-RRB-

podocyte

apoptosis/loss

and

exposed

glomerular

basement

membrane

-LRB-

-RRB-

filtration

of

non-specific

plasma

proteins

-LRB-

-RRB-

capillary

expansion

-LRB-

-RRB-

formation

of

synechiae

-LRB-

-RRB-

misdirected

filtration

at

points

of

synechiae

-LRB-

-RRB-

mesangial

matrix

proliferation

Adapted

from

Kwoh

et

al.

-LSB-

-RSB-

However

unlike

other

causes

of

proteinuria

and

nephrotic

syndrome

such

as

minimal

change

disease

-LRB-

MCD

-RRB-

FSGS

often

progresses

to

ESKD

While

foot

process

effacement

is

seen

in

MCD

as

well

as

FSGS

histologically

FSGS

is

characterized

by

increased

extracellular

matrix

within

the

glomerular

tuft

with

obliteration

of

the

glomerular

capillary

lumen

These

sclerotic

lesions

occur

focally

and

in

only

some

segments

of

glomeruli

and

are

typically

not

associated

with

immune

complex

deposition

-LSB-

-RSB-

The

location

of

sclerotic

lesions

by

light

microscopy

defines

the

variants

of

FSGS

perihilar

variant

-LRB-

with

sclerosis

of

the

vascular

pole

-RRB-

cellular

variant

-LRB-

associated

with

hypercellularity

of

the

capillary

space

-RRB-

tip

variant

-LRB-

involving

the

part

of

the

glomerulus

near

the

origin

of

the

proximal

tubule

-RRB-

and

collapsing

variant

-LRB-

with

one

or

more

glomeruli

with

global

or

segmental

collapse

-RRB-

-LSB-

-RSB-

Clinically

the

variants

of

FSGS

differ

for

example

the

collapsing

variant

tends

to

progress

more

rapidly

to

ESKD

and

commonly

occurs

in

the

setting

of

HIV

-LSB-

-RSB-

It

is

possible

that

different

mechanisms

may

play

a

role

in

the

pathogenesis

of

each

variant

of

FSGS

-LSB-

-RSB-

Insight

into

the

pathogenesis

of

FSGS

developed

over

the

past

decade

from

studies

of

genetic

mutations

in

mice

models

of

progressive

glomerulosclerosis

-LRB-

such

as

the

rat

remnant

kidney

model

-RRB-

and

identification

of

gene

mutations

in

some

familial

forms

of

nephrotic

syndrome

-LRB-

including

congenital

nephrotic

syndrome

and

familial

and

autosomal

dominant

FSGS

-RRB-

-LSB-

-RSB-

Key

in

the

pathogenesis

of

FSGS

is

podocyte

damage

and

loss

-LSB-

-RSB-

Injury

to

podocytes

occurs

by

four

major

mechanisms

alteration

of

the

components

of

the

slit

diaphragm

or

interference

with

its

structure

dysregulation

of

the

actin

cytoskeleton

alteration

of

the

glomerular

basement

membrane

or

its

interactions

with

the

podocyte

or

alteration

of

the

negative

surface

charge

of

the

podocyte

-LSB-

-RSB-

Damage

to

podocytes

triggers

apoptosis

and

their

detachment

of

podocytes

from

the

glomerular

basement

membrane

-LSB-

-RSB-

The

ensuing

reduction

in

podocyte

number

is

felt

to

play

an

important

role

in

the

pathogenesis

of

FSGS

-LSB-

-RSB-

The

podocyte

is

normally

a

terminally

differentiated

cell

with

limited

proliferative

capacity

in

response

to

injury

-LSB-

-RSB-

The

initial

insult

to

the

podocyte

leads

to

further

damage

mediated

by

cytokine

release

mechanical

stress

and

further

loss

of

polarity

resulting

in

sclerosis

and

scarring

of

the

glomerulus

-LSB-

-RSB-

Genetic

mutations

seen

in

congenital

forms

of

nephrotic

syndrome

and

FSGS

enabled

researchers

to

identify

specific

gene

mutations

involved

in

podocyte

damage

-LSB-

-RSB-

Mutations

of

the

nephrin

gene

a

podocyte-specific

transmembrane

component

of

the

slit

diaphragm

are

found

in

congenital

Finnish-type

nephrotic

syndrome

and

may

lead

to

loss

of

normal

caliber

slit

diaphragms

-LSB-

-RSB-

In

mouse

models

mutations

of

nephrin-like

transmembrane

genes

-LRB-

-RRB-

which

also

localize

to

the

slit

diaphragm

result

in

proteinuria

and

early

death

-LSB-

-RSB-

It

is

unclear

how

alteration

of

the

slit

diaphragm

results

in

podocyte

loss

The

slit

diaphragm

may

be

integral

to

maintaining

cell

polarity

or

its

damage

may

alter

the

balance

of

cell

signals

resulting

in

apoptosis

Mutations

in

a

Fyn

kinase

-LRB-

one

of

the

src

tyrosine

kinases

-RRB-

that

phosphorylates

nephrin

and

may

regulate

cell

cycle

and

apoptosis

resulted

in

proteinuria

and

foot

process

effacement

in

a

mouse

model

-LSB-

-RSB-

Other

proteins

which

are

part

of

the

slit

diaphragm

complex

include

podocin

protein

-LRB-

-RRB-

FAT

P-cadherin

an

LAP

-LRB-

leucine

rich

repeat

and

PDZ

domain

-RRB-

protein

and

-LSB-

-RSB-

Mutations

in

podocin

-LRB-

a

transmembrane

protein

that

interacts

with

nephrin

and

-RRB-

have

been

identified

in

familial

FSGS

-LSB-

-RSB-

Recently

mutations

in

an

immunoglobulin-like

protein

that

is

involved

in

nephrin

integration

with

the

podocyte

cytoskeleton

have

also

been

linked

to

genetic

forms

of

FSGS

-LSB-

-RSB-

In

mouse

models

the

loss

of

and

-LRB-

transmembrane

proteins

with

cadherin-like

repeats

-RRB-

results

in

the

absence

of

slit

diaphragms

proteinuria

and

early

death

-LSB-

-RSB-

The

role

of

the

other

components

of

the

slit

diaphragm

in

the

pathophysiology

of

FSGS

is

not

yet

clear

an

important

structural

component

of

the

podocyte

cytoskeleton

is

mutated

in

some

autosomal

dominant

forms

of

FSGS

-LSB-

-RSB-

Other

mutations

have

been

identified

in

association

with

FSGS

in

addition

to

abnormal

structural

proteins

For

example

is

a

cation-selective

ion-channel

protein

that

mediates

calcium

signals

and

has

also

been

associated

with

FSGS

-LSB-

-RSB-

Certain

clinical

variants

of

FSGS

are

suggestive

of

different

mechanisms

of

injury

to

the

podocyte

For

example

a

circulating

factor

which

leads

to

glomerular

basement

membrane

injury

has

been

proposed

in

the

pathogenesis

of

some

types

of

FSGS

-LSB-

-RSB-

For

example

there

appears

to

be

a

role

of

a

circulatory

factor

in

the

recurrence

of

FSGS

in

transplanted

kidneys

-LSB-

-RSB-

In

some

patients

with

recurrent

FSGS

proteinuria

remits

in

response

to

plasmapheresis

and

the

removal

of

serum

proteins

In

addition

injections

of

serum

from

patients

with

recurrent

FSGS

were

capable

of

inducing

proteinuria

in

rats

-LSB-

-RSB-

Another

example

of

alternative

mechanisms

of

injury

is

collapsing

FSGS

which

occurs

in

the

setting

of

viruses

such

as

HIV

In

collapsing

FSGS

dysregulation

of

the

podocyte

cell

cycle

appears

to

result

in

immature

proliferative

podocytes

-LSB-

-RSB-

Finally

recent

work

has

focused

on

the

role

of

the

parietal

epithelial

cell

in

the

pathophysiology

of

FSGS

-LSB-

-RSB-

Proliferation

of

parietal

epithelial

cells

was

identified

in

both

a

transgenic

model

of

FSGS

and

a

biopsy

from

a

patient

with

collapsing

FSGS

-LSB-

-RSB-

Of

great

clinical

importance

is

the

mechanism

by

which

the

initial

podocyte

injury

progresses

to

the

final

sclerotic

lesion

-LRB-

Fig.

-RRB-

As

podocyte

numbers

decline

there

is

a

relative

exposure

of

the

glomerular

basement

membrane

Maladaptive

interactions

develop

between

the

glomerular

basement

membrane

and

the

parietal

epithelial

cells

Expansion

of

synechiae

and/or

the

leak

of

protein

into

Bowman

's

space

results

in

the

deposition

of

collagen

Ultimately

this

results

in

the

collapse

of

the

capillary

loop

and

the

loss

of

endothelial

cells

-LSB-

-RSB-

Factors

resulting

in

the

progression

of

FSGS

to

ESKD

have

also

been

the

focus

of

recent

research

-LRB-

Fig.

-RRB-

Cytokines

and

vasoactive

factors

are

believed

to

play

a

major

role

in

the

progression

of

FSGS

The

overexpression

of

transforming

growth

factor

β

-LRB-

TGFβ

-RRB-

or

its

effector

proteins

the

Smads

leads

to

glomerulosclerosis

in

animal

models

-LSB-

-RSB-

Activation

of

the

renin-angiotensin

system

upregulates

TGFβ

and

is

felt

to

further

lead

to

the

progression

of

disease

-LSB-

-RSB-

Other

angiogenic

factors

such

as

platelet-derived

growth

factor

-LRB-

PDGF

-RRB-

and

vascular

endothelial

growth

factor

-LRB-

VEGF

-RRB-

may

also

play

a

role

in

disease

progression

-LSB-

-RSB-

The

evidence

for

this

is

primarily

based

on

animal

models

of

progressive

glomerulosclerosis

such

as

the

rat

remnant

kidney

model

In

this

model

PDGF

and

VEGF

are

upregulated

and

the

later

loss

of

VEGF

expression

correlates

with

progression

of

the

glomerulosclerosis

-LSB-

-RSB-

Fig.

involved

in

the

progression

of

FSGS

to

end-stage

kidney

disease

-LRB-

ESKD

-RRB-

initial

loss

or

injury

to

podocytes

-LRB-

related

to

defects

in

membrane

proteins

or

cytoskeleton

instability

-RRB-

leads

to

cytokine

release

mechanical

stress

hyperfiltration

and

glomerular

hypertrophy

These

factors

lead

to

upregulation

of

an

inflammatory

response

mediated

by

monocytes

macrophages

and

T-cells

The

end

result

is

collagen

matrix

deposition

and

fibrosis

and

progression

to

ESKD

Mechanical

stress

is

also

believed

to

play

a

role

in

the

progression

of

FSGS

-LSB-

-RSB-

Increased

filtration

due

the

defects

of

the

filtration

barrier

results

in

increased

single-nephron

glomerular

filtration

rate

-LRB-

SNGFR

-RRB-

This

hyperfiltration

results

in

hypertrophy

of

glomeruli

The

hypertrophy

exacerbates

the

mismatch

between

the

glomerular

basement

membrane

and

the

decreased

numbers

of

podocytes

resulting

in

further

injury

-LSB-

-RSB-

Another

factor

in

the

progression

of

FSGS

is

tubulointerstitial

injury

Clinically

tubulointerstitial

injury

is

a

predictor

of

the

loss

of

renal

function

in

FSGS

-LSB-

-RSB-

The

nonspecific

entry

of

proteins

into

the

tubular

lumen

is

one

potential

source

of

damage

to

the

interstitium

Indeed

persistence

of

nephrotic-range

proteinuria

is

a

negative

prognostic

factor

for

the

progression

of

FSGS

to

ESKD

-LSB-

-RSB-

While

it

is

unclear

if

proteinuria

itself

is

toxic

to

the

tubulointerstitium

decreases

in

proteinuria

achieved

by

angiotensin-converting

enzyme

-LRB-

ACE

-RRB-

inhibitors

and

by

angiotensin

receptor

blockers

-LRB-

ARB

-RRB-

appear

to

slow

disease

progression

in

some

adults

with

FSGS

-LSB-

-RSB-

The

presence

of

plasma

proteins

in

the

tubular

filtrate

may

directly

injure

the

tubulointerstitium

Cytokines

-LRB-

such

as

TGFβ

-RRB-

when

present

in

the

tubules

will

recruit

monocytes

macrophage

and

T-cells

This

stimulates

other

cytokines

including

tumor

necrosis

factor

alpha

and

other

chemokines

-LSB-

-RSB-

The

inflammatory

infiltrate

leads

to

mesangial

matrix

deposition

promoting

the

collapse

of

glomeruli

The

cellular

infiltrate

and

cytokines

also

damage

tubular

epithelial

cells

and

some

tubular

epithelial

cells

may

undergo

transformation

to

mesenchymal

cells

-LRB-

an

epithelial-mesenchymal

transition

or

EMT

-RRB-

-LSB-

-RSB-

These

mesenchymal

cells

as

well

as

recruited

and

stimulated

fibroblasts

result

in

collagen

matrix

deposition

and

tubulointerstitial

fibrosis

-LSB-

-RSB-

The

beneficial

effects

of

blocking

the

renin-angiotensin

system

may

not

be

limited

to

their

antiproteinuric

or

antihypertensive

effects

As

noted

earlier

angiotensin

stimulates

TGFβ

contributing

to

fibrosis

It

can

also

induce

oxidative

stress

and

it

is

stimulated

by

mechanical

stress

such

as

hyperfiltration

-LSB-

-RSB-

In

addition

angiotensin

affects

intracellular

calcium

concentrations

and

the

podocyte

cytoskeleton

-LSB-

-RSB-

Inhibition

of

angiotensin

may

slow

progression

by

these

local

mechanisms

-LSB-

-RSB-

With

the

increasing

incidence

of

FSGS

in

children

-LSB-

-RSB-

these

pathways

of

podocyte

injury

and

disease

progression

provide

important

targets

for

future

intervention

Trials

have

already

been

initiated

to

antagonize

cytokines

such

as

TGFβ

Future

therapeutic

targets

may

include

factors

involved

in

podocyte

protection

or

tubulointerstitial

injury

Questions

-LRB-

Answers

appear

following

the

reference

list

-RRB-

Which

of

the

following

statements

is

TRUE

regarding

the

current

understanding

of

the

pathogenesis

of

focal

segmental

glomerulosclerosis

-LRB-

FSGS

-RRB-

FSGS

may

result

from

immune-complex-mediated

damage

to

endothelial

cellsAlterations

in

components

of

the

slit

diaphragm

may

play

a

role

in

the

pathogenesis

of

FSGSProliferation

of

podocytes

leads

to

cytokine

release

and

mechanical

stress

resulting

in

scarring

and

sclerosis

of

the

glomeruliMutations

in

a

chloride

channel

have

been

associated

with

FSGS

and

may

be

pathogenicAll

of

the

following

are

mutations

of

structural

proteins

that

have

been

identified

as

pathogenic

in

FSGS

EXCEPT

Sodium

channel

of

FSGS

to

end-stage

kidney

disease

-LRB-

ESKD

-RRB-

results

from

Downregulation

of

transforming

growth

factor

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

nephrotic syndrome
pathophysiology
podocyte
injury
animal models
nephrin
podocin
tubulointerstitial

focal segmental glomerulosclerosis (fsgs)


Development and application of a Japanese model of the WHO fracture risk assessment tool -LRB- FRAX ™ -RRB- Summary The present study estimated the 10-year probability using the Japanese version of WHO fracture risk assessment tool -LRB- FRAX ™ -RRB- in order to determine fracture probabilities that correspond to intervention thresholds currently used in Japan and to resolve some issues for its use in Japan . Introduction Fractures related to osteoporosis have become a major health and economic burden in Asian countries just as they have in North America and Europe . An estimated 117,900 cases of hip fracture occurred in 2002 -LSB- 1 -RSB- , and the incidence in Japan has increased in the past 10 years -LSB- 1 , 2 -RSB- . Asia will be expected to have the highest absolute increase in fracture number because it has the largest population . Early detection of individuals with high fracture risk using clinical risk factors would have a substantial impact on reducing the burden of fractures in Asia . A series of meta-analyses on prospective population-based cohorts has identified a number of clinical risk factors that contribute to fracture risk independently of BMD at the femoral neck -LSB- 3 -RSB- . The integration of these risks would , therefore , enhance the predictive value of BMD -LSB- 4 -RSB- . The risk factors comprise age , sex , bone mineral density , body mass index -LRB- BMI -RRB- , long-term use of glucocorticoids , parental history of hip fracture , history of fragility fracture , smoking , alcohol consumption -LRB- 3 or more units/day -RRB- , and secondary osteoporosis such as rheumatoid arthritis . A WHO scientific group has proposed that the 10-year probability for fracture is used to express fracture risk for clinical assessment -LSB- 5 -RSB- and to determine intervention thresholds -LSB- 3 -RSB- The aim of this study was to create a fracture probability model based on the methodology of the WHO risk assessment tool -LRB- FRAX ™ -RRB- -LSB- 6 -RSB- calibrated to the epidemiology of Japan . In addition , several problems need to be resolved before the FRAX ™ model is applied to Japan . First , the FRAX ™ tool inputs femoral neck BMD and the Z-score or T-score is based on the NHANES III reference data base . In Japan , BMD at the lumbar spine is widely used clinically because the physical size of Japanese people is smaller than that of Western people , giving rise to a view based on little evidence that the reproducibility of measurements at the femoral neck BMD would be poorer than that at the lumbar spine . Furthermore , data on the young adult mean -LRB- YAM -RRB- and the mean at each age are installed in the DXA systems in Japan , and programmed to calculate T - and Z-scores from Japanese reference data . In addition , the Japanese Society for Bone and Mineral Research -LSB- 7 , 8 -RSB- provide recommendations for the diagnosis of osteoporosis and intervention based on YAM , and these are widely used in clinical practice . Against this background , additional aims of the present study were to provide fracture probabilities based on the FRAX ™ tool that were equivalent to currently accepted intervention thresholds , explore the impact of using Japanese-specific normative data for femoral neck BMD , and reassess the respective performance characteristics of BMD at the femoral neck and lumbar spine . Methods Models were constructed to compute the 10-year probability of hip fracture and a major osteoporosis-related fracture in Japan . A major osteoporosis-related fracture was defined as a clinical spine , hip , proximal humeral and forearm fracture . Poisson modelling was used to calculate the hazard functions . The relationship between probability and hazard functions were used to calculate the 10-year probability or fracture for a combination of the risk factors . The mortality estimates for Japan were those published by the World Health Organization for 1999 , which accord with estimates from Japan -LSB- 9 -RSB- . The incidence of hip fractures was taken from previously published sources -LSB- 1 -RSB- as was the incidence of fractures at the proximal humerus and distal forearm -LSB- 10 -RSB- . Since the incidence of a clinical vertebral fracture was not known in Japan , we assumed that the ratio of clinical vertebral fracture incidence to that of a vertebral fracture diagnosed by radiographic surveys -LSB- 11 -RSB- would be the same in the Japan as it was for Sweden -LSB- 12 -RSB- . The relationship of clinical risk factors to fracture outcomes was assumed to be the same as that determined in a large meta-analysis of risk factors of 190,000 patient years from nine prospectively studied population-based cohorts from Europe , Australia , North America and Asia -LSB- 3 -RSB- . The relationship has been validated in a further 11 cohorts of population-based samples with 1.2 million patient years of observation from the same regions -LSB- 4 -RSB- . The independent contribution of each risk factor was used to compute probabilities of fracture in the absence of clinical risk factors or in the presence of any combination -LSB- 13 , 14 -RSB- . In Japan , the criteria for the diagnosis of osteoporosis prepared by the Japanese Society for Bone and Mineral Research -LSB- 7 -RSB- are based on BMD measurements expressed as a percentages of the young adult mean -LRB- YAM -RRB- for women . In patients with no prior fragility fracture a diagnosis of osteoporosis is made where the BMD is less than 70 % of YAM . In patients with a previous fracture , osteoporosis is diagnosed where the BMD is less than 80 % of YAM . These diagnostic thresholds , derived by maximising sensitivity and specificity for fracture detection , are also used as intervention thresholds . In order to compare intervention thresholds using YAM with probabilities derived from the FRAX ™ algorithm , T-score equivalents were used . The T-score equivalent to 70 % and 80 % of YAM for Japanese people is − 2.7 SD and − 1.8 SD , respectively , using the NHANES III reference for BMD at the femoral neck in Caucasian women aged 20 -- 29 years -LSB- 15 -RSB- . The relative performance characteristics of BMD at the lumbar spine and femoral neck were examined in a population-based prospective study in Hiroshima . The Hiroshima cohort comprised 2,596 men and women -LRB- 69 % female , 9,803 person years , mean age 65.1 years -RRB- . Details of the cohort have been previously published -LSB- 11 -RSB- . In brief , the participants received measurement of lumbar spine and femoral neck BMD using dual X-ray absorptiometry -LRB- DXA , QDR-2000 , Hologic -RRB- during the period from 1994 to 1995 and were followed for a mean period of 4 years . Information about hip fracture , fracture of the distal radius , proximal humeral fracture and clinical spinal fracture was collected at interview by trained nurses and physicians during the biennial health examinations . One hundred eighty-six fractures were detected during the follow-up period , of which 89 were categorized as osteoporotic fractures and 31 were hip fractures . The gradient of fracture risk -LRB- increase in fracture risk per SD change in Z-score for BMD and increase in fracture risk per 0.1 g/cm2 change in BMD -RRB- at the two sites was determined by the use of Poisson models -LSB- 16 -RSB- . The fracture outcomes were calculated for hip fracture , a major osteoporosis-related fracture -LRB- femoral neck , distal radius , proximal humerus and clinical spine fracture -RRB- and all fractures . The mean height and body weight for Japanese women in the Hiroshima cohort was 150 cm and 52.6 kg , respectively , giving a BMI of 23.4 kg/m2 . The calculation of fracture probability was made at this BMI , but differences in BMI have little effect on predictive value for fracture risk assessment in the presence of BMD -LSB- 17 -RSB- . Japanese-specific T - and Z-scores and those derived from NHANES III were compared using the database of the Japanese Society for Bone and Mineral Research -LSB- 7 -RSB- . Data using both methods of calculation were entered into the FRAX ™ tool . Results Ten-year probability of fracture The 10-year probability of a major osteoporotic fracture for individuals without clinical risk factors is shown in Fig. 1 grouped by sex , age and T-score . The 10-year probability increased with age and with decreasing T-score . At younger ages , the fracture probability was similar in men and women . With advancing age , probabilities rose as expected , but the increase was greater in women than in men . In men aged 80 years , the 10-year probability for osteoporosis-related fracture exceeded 10 % at a T-score of − 3 SD , whereas in women of the same age , fracture probabilities exceeded 10 % with T-score of − 1 SD . Fig. 1Ten-year probability -LRB- % -RRB- of osteoporotic fracture -LRB- hip , clinical spine , humerus , forearm -RRB- in Japanese men and women without clinical risk factors according to age and T-score for BMD at the femoral neck The contribution of clinical risk factors to fracture probability is shown in Fig. 2 for women aged 65 years with a BMI of 23.4 kg/m2 . In women without clinical risk factors , the 10-year probability for an osteoporosis-related fracture was 7.5 % . The 10-year probability was higher in the presence of clinical risk factors . Smoking and alcohol were relatively weak risk factors , the use of long-term glucocorticoids of intermediate weight , and a parental history of hip fracture or a prior fragility fracture were associated with the highest risks . For example , the 10-year probability was 8.1 % for smokers and 14.5 % for individuals with a prior fracture . The 10-year probability for hip fracture was 1.1 % in women without a clinical risk factor , 1.6 % in smokers and 2.7 % in women with a previous fracture -LRB- see Fig. 2 -RRB- . Fig. 2Ten-year probability for osteoporotic -LRB- hip , clinical spine , humerus , forearm -RRB- and hip fracture -LRB- % -RRB- according to the presence of a clinical risk factor , in women at the age of 65 years and with a BMI of 23.4 kg/m2 Fracture probabilities were computed in women at the diagnostic threshold recommended in Japan . Thus , the cut-off level of BMD was set at 70 % of YAM in women without a previous fracture and at 80 % of YAM in those with a previous fragility fracture . In women aged 50 , 60 , 70 and 80 years without clinical risk factors and with BMD equivalent to 70 % of YAM , the 10-year probability was 5.4 % , 8.7 % , 13.8 % and 23 % , respectively . In women having BMD equivalent to 80 % of YAM and existing fracture but no other clinical risk factors , the 10-year probability was 7.1 % , 10.5 % , 14.7 % and 23.4 % at the same ages , respectively . Thus , at each age , the fracture probability was similar using the two diagnostic criteria . In contrast , the fracture probability equivalent to the diagnostic threshold in Japan rose with age , and at the age of 80 years was about four times higher than that at age 50 years -LRB- Fig. 3 -RRB- . Similar findings were apparent for hip fracture probability in that probabilities equivalent to the diagnostic threshold in Japan rose with age . The increase with age was more marked than for all major fractures and at the age of 80 years was about 6 -- 40 times higher than that at age 50 years depending on the threshold used -LRB- see Fig. 3 -RRB- . Fig. 3Ten-year probability of osteoporotic -LRB- hip , clinical spine , humerus , forearm -RRB- and hip fracture based on women at the threshold for the diagnosis of osteoporosis using the criteria of the Japanese Bone Mineral Metabolism Association Comparison of lumbar spine and femoral neck BMD The gradient of fracture risk for spine BMD and femoral neck BMD in the Hiroshima cohort indicated that lumbar spine measurements predicted all fractures , osteoporosis-related fracture and hip fracture with approximately equal gradients of risk that ranged from 1.25 / SD for all fractures to 1.17 / SD for hip fractures . There was no difference in the gradient of risk between men and women . In the case of hip fracture risk , the gradient of risk in men and women combined was not statistically significant with BMD measured at the lumbar spine . BMD at femoral neck had a similar or slightly higher gradient of risk for fractures compared with spine BMD , particularly in the case of hip fracture -LRB- Table 1 -RRB- . There was no significant difference in gradient of risk between lumbar spine BMD and femoral neck BMD with the exception of that for hip fracture where the gradient of risk was significantly higher for measurements made at the femoral neck . When gradient of risk was standardized to a constant denominator -LRB- i.e. , RR/0 .1 g/cm2 -RRB- the findings remained unchanged -LRB- see Table 1 -RRB- . Table 1Predictive ability of spine and femoral neck BMD for any , osteoporotic and hip fracture in men and women from Japan RR/SDRR/0 .1 g/cm2RR95 % CIRR95 % CIa . Any fractureFemoral neck1 .451.23 -- 1.701.431.22 -- 1.68 Lumbar spine1 .251.13 -- 1.391.381.19 -- 1.61 b. Osteoporosis-related fracturesFemoral neck1 .401.09 -- 1.781.381.09 -- 1.74 Lumbar spine1 .201.04 -- 1.401.301.05 -- 1.61 c. Hip fractureFemoral neck2 .08 b1 .34 -- 3.222.111.38 -- 3.23 Lumbar spine1 .170.91 -- 1.501.250.87 -- 1.80 a Hip , clinical spine , forearm and proximal humerusb Significantly higher than lumbar spine -LRB- = 0.049 -RRB- Japanese reference values The reference mean in women aged 20 -- 29 years at the femoral neck was 0.858 g/cm2 -LRB- SD = 0.120 g/cm2 -RRB- using the NHANES III data . When young normal values were computed from the Japanese population the mean BMD was 0.786 g/cm2 -LRB- SD = 0.107 g/cm2 -RRB- . Thus the threshold for osteoporosis using the NHANES III data was 0.558 g/cm2 and that derived from the Japanese data was 0.519 g/cm2 . The thresholds for osteopenia -LRB- WHO definition -RRB- were 0.738 g/cm2 and 0.679 g/cm2 , respectively . Thus there were systematic differences in the T-score derived from the two data sets . A comparison of fracture probabilities computed from the z-scores using the two approaches is shown in Fig. 4 for different combinations of risk factors . The differences in probabilities were relatively modest , but as expected , the use of Japanese reference values overestimated fracture probabilities . Fig. 4Correlation between 10-year fracture probabilities -LRB- % -RRB- in women without clinical risk factors computed from normative data using NHANES III reference values and Japanese-derived reference values for femoral neck BMD . BMI is set at 23.4 kg/m2 Discussion This paper describes the development of the WHO fracture risk assessment tool calibrated to the epidemiology of Japan . The incidence of hip fracture , distal radius fracture and proximal humeral fracture in Japan is lower than that in North America or Northern Europe -LSB- 1 , 10 -RSB- . However , the prevalence and incidence of spinal fracture are higher in Japan -LSB- 11 , 18 -RSB- . A minority of all cases of morphological spinal fracture are assumed to be clinical spine fractures in the Japanese FRAX ™ models . The multiplier is age and sex specific . For men the multiplier goes from approximately 33 % at age 50 to 48 % at age 85 . For women the corresponding figures are 19 % and 24 % . These estimates , derived from the epidemiology of fracture in Sweden -LSB- 12 -RSB- , have been shown to hold true for Japan -LSB- 19 -RSB- . The FRAX ™ algorithm is suitable for assessment in men and women from the age of 40 years and calculates the 10-year probability for both hip fracture and a major osteoporosis-related fracture . One of its strengths is that it can capture the independent contribution of several clinical risk factors to fracture risk and can be used with or without information on femoral neck BMD . A more detailed account of the properties of the FRAX ™ models is provided elsewhere -LSB- 13 -RSB- . In this paper , we focused on its application to decision-making in clinical practice with the estimation of intervention threshold i.e. , the fracture probability at which intervention is currently considered to be worthwhile . The approach should be distinguished from intervention thresholds that are based on health economic analysis . The WHO makes no specific recommendation concerning intervention thresholds , since these depend on many local factors -LSB- 6 -RSB- . Rather , it is suggested they should be determined by each country , based on the local healthcare situation and cost-effectiveness of the treatment of osteoporosis . Intervention thresholds , based on cost-effectiveness have been formulated in the UK , the USA and in Sweden -LSB- 20 -- 22 -RSB- . In Japan , diagnostic thresholds are used as intervention thresholds . When the probabilities of osteoporosis-related fracture were determined at these thresholds , they varied with age -LRB- see Fig. 3 -RRB- , ranging from approximately 5 % at the age of 50 years to more than 20 % at the age of 80 years . Against this background , a 10-year probability of 10 % for osteoporosis-related fracture may be an acceptable intervention threshold for Japan , though an optimization should take account of health economic consequences for individuals and for the health care budget . The FRAX ™ tools are designed to be extensively used in the world as a means of identifying individuals with elevated risk for fracture and aid in the determination of the threshold for therapeutic intervention , but there will be hurdles to be faced in the ease of its acceptance . Such hurdles are likely to differ from country to country . In Japan , the choice of clinical risk factors is not at issue since the risk factors adopted in the FRAX ™ algorithms included the data from the Hiroshima cohort , Japan -LSB- 11 , 23 , 24 -RSB- , and the validation included the Japanese Miyama cohort -LSB- 13 -RSB- . More problematic is the inclusion of femoral neck BMD , since the lumbar spine measurement is the most widely used in Japan . Asian physiques are smaller than those of Caucasians , and the geometric characteristics of the femoral neck in Japanese differ from those in American women , in that the femoral neck length is shorter than in the Japanese -LSB- 25 , 26 -RSB- . Because of uncertainty regarding measurement of femoral neck BMD , measurement of lumbar BMD is widely used in Japan . The present study indicates that concerns over the use of femoral neck BMD are unfounded . Femoral neck BMD was superior in its ability to predict hip fractures compared with spine BMD , and BMD at the spine and femoral neck had similar predictive value for fractures other than hip fracture . Fujiwara et al. -LSB- 11 -RSB- have also shown that the ability to predict the risk for morphological spinal fracture was similar between femoral neck BMD and lumbar spine BMD . These data on gradients of fracture risk , derived in Japan , did not differ from those reported in Western countries . Indeed , the meta-analysis used to inform the FRAX ™ tool showed no evidence for heterogeneity in gradients of risk between cohorts -LSB- 16 -RSB- . Thus the evidence suggests that fracture risk assessment is not disadvantaged by the use of femoral neck BMD . Indeed , the converse may be true . A further hurdle , unique to Japan , is that diagnostic thresholds differ from the WHO description of osteoporosis which defines osteoporosis on the basis of a fixed T-score threshold -LRB- ≤ − 2.5 SD -RRB- using an international reference standard for young -LRB- aged 20 -- 29 years -RRB- Caucasian women -LSB- 15 -RSB- . In Japan , diagnostic thresholds are also derived by reference to a young population , but differ from the WHO in that a local -LRB- i.e. , Japanese -RRB- standard is used and that the criteria differ in patients with or without previous fracture . In view of the widespread use of data derived from the Japanese population , the question arises whether T-scores or Z-scores derived from Japanese databases could be used in the FRAX ™ tool , rather than those derived from the international reference base . In the present study , mean BMD at the femoral neck was lower in Japanese women than in the NHANES III sample from the USA , as previously shown -LSB- 27 -RSB- . The difference was not , however , large -LRB- approximately a half a SD -RRB- . There were also differences in the SD which was smaller in Japanese women than in the NHANES III sample -LRB- 0.107 and 0.120 g/cm2 , respectively -RRB- . Not surprisingly , the DXA-based T-score obtained from Japanese and USA populations differed as did the computed probabilities . Although the differences were small at low T-scores , when applying the FRAX ™ model to Japan , it is preferable to program the system so that the Japanese T - and Z-scores are converted into the appropriate T - and Z-scores based on NHANES III . In conclusion , a FRAX ™ tool has been developed to compute fracture probabilities calibrated to the epidemiology of Japan . The tool has been used to determine possible thresholds for therapeutic intervention , based on equivalence of risk with current guidelines . The approach will need to be supported by appropriate health economic analyses . The present study indicates that the femoral neck BMD is suitable for prediction of the risk for fracture among Japanese people . However , when applying the FRAX ™ model to Japan , T-scores and Z-scores should be converted into those derived from the international reference .

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

bone mineral density
fracture
intervention thresholds
japan

fracture probability
fracture risk assessment tool