DISEASEOF THE MONTH

Treatment of the Idiopathic and Outcomes in Children

BRUCE
*Dit,jsio,z of Pediatric

Nephrotic and Adults

A. MENDOZAt
University
San

Syndrome:

Regimens

M. TUNE*
of Pediatric Nephrologv,

and
Nephrologv,

STANLEY
Stanford
of Cal fornia,

School
Diego,

ofMedicine,
School

Stanford,
San

California;
Diego,

and
California.

the tDivision

Universits

ofMedicine,

The uria, mon The

eases

nephrotic

syndrome

(NS). edema,

consisting and

of massive

proteinis a comand adults. renal disbegins with

hypoalbuminemia.

hyperlipidemia,

Edema The
NS allows creased renal

traditional
a decrease aldosterone salt and water serum extravasation

view
of and

has

been

that
resulting

massive
oncotic in hormone with above

albuminuria
pressure, hypovolemia, secretion, this 2.0 mechanism which

in
inand

complication of gbomerular authors personal experience

of children. pediatric (MCD) and Therefore, NS, focal the with

disease in children involves mainly

present emphasis segmental discussion on

causes

in intravascular fluid, antidiuretic Consistent levels are

idiopathic disease

minimal-change

retention.

glomerulosclerosis

are the observations regithose

occurs when

that,
albumin

in MCD

of childhood,

edema
g/dL

seldom
and the

(FSGS). mens, and for children.

Presenting outcomes

features, for adults

complications, are then

treatment compared with

elevated during salt-poor

hematocrit, relapse may albumin. against

to respond

prerenal azotemia, and be improved by intravenous this model diuresis

albumin are levels and typically normal are edema. (2) includes the

fluid retention infusions of

failure of some the

Etiology
The
system association

Evidence primary
in pediatric between

causes
evidence MCD

of idiopathic
pointing
( 1 ).

NS are
to MCD a role

not known.
of the

There
immune

patients

to intravenously

administered

albumin,

is circumstantial

fact an
of matic tions renin with genital

that
rise that and heavy

steroid-induced
in serum plasma aldosterone proteinuria volumes

often

occurs
and to increased in or

before
the and many no fraction. with edema.

a draobservaplasma patients conAn

Several
and

reports

have

described
Relapses

concentration, decreased Finally. have little filtration

allergy

in children.

the syndrome

are triggered

commonly

by minor

infections

and

occasionally by reactions malities of both humoral

to bee stings or poison ivy. Abnorand cellular immunity have also been by corticosteprovides mdiof these observaimmunologically

patients

analbuminemia

described. Finally. the induction of remissions roid, alkylating agent, or cycbosporine therapy rect
tions,

alternative
a decreased

explanation
GFR, with

for retention
a decreased

of salt and

water

in NS

is

evidence
however,

for an immune
provides direct

etiology.
evidence

None
of

mediated

pathogenesis.

Natural
Before
40%

History
the availability
with NS

of
died etc.),

antibiotics
of infections

and failure, of
of

corticosteroids,
septice-

Pathophysiology
Proteinuria Children with have a generalized clearance than
This

of children

(bacterial

mia, MCD, although massively proteinuric, gbomerular leak to macromolecules macromolecules a range
other lines in the by which these

peritonitis.

cellulitis, (3,4).
agents increased

renal advent
the rate

or occasionally and
from

do not ( 1 ). The less the

thromboembolism
antimicrobial

The

penicillin
survival

other
acute

of neutral over of anionic

several

in MCD radii.
suggest

is actually In contrast,

infections. and chronic

survived,

However, renal
sustained

massive failure
spontaneous

edema,

recurrent common.

septic If the
often

events, children
occurred

normal
and

of molecular
of evidence

remained activity. therapy dramatic

occurred majority

clearance uria results

macromolecules

is significantly
that wall has

increased.
protein-

remissions

from

a loss of the fixed

glomerular charges

negative
are

charges
lost

of anionic
(1). not The been

only after years of disease In the early 1950s, oral (hereafter ment
steroid disappearance therapy

with was

adrenal introduced benefit

within

corticosteroids in the Diuresis

Many

glycosaminoglycans mechanism

capillary

designated NS,
for the

as steroids) with
great

treatand
who

of idiopathic

(4).

defined. children
genic

A highly with
significance

cationic has been

of this

protein recently
protein

in the plasma described,

not been has

and

urine

of

of proteinuria

4 weeks

of daily

MCD

but the pathodetermined.

of children.

responded, most of whom must have had and responded to retreatment. Alkylating

MCD (5,6), relapsed agent therapy with time cortibecause of

agents were

Correspondence G-3()6. Stanford

to Dr. Bruce M. Tune. Division of Pediatric Nephrology. University School of Medicine, Stanford. CA 94305-5119.

mechborethamine was successfully tried about the sone was introduced ( 1 ) but was quickly abandoned
its (7). acute toxicity. Better-tolerated oral alkylating

1046-6673/0805-0824$03.0()/0

Journal of the American Society of Nephrobogy Copyright 0 1997 by the American Society of Nephrology

introduced Although

later

in children steroids and

with alkylating

steroid

toxicity

or resistance immuno-

agents

are both

Treatment

of NS

825

suppressive,

the

frequency

of

infectious

complications

was

logic

experience,

newly

diagnosed,

uncomplicated

pediatric

L1i:llhi1llhId ILkltkkkl il1 ,;

The International Childhood
In
ease

01
Study

. dI th I( 1i1i N .
Disease in

(. st s
biopsy. have

tf

a 1t; t t1t 1 llLthtkj

who Renal respond biopsy is with

1JIIk oi al S1&?IOitlS without a

to this reserved features treatment for suggestive are children of assumed who

renal
to are

Patients MCD.

of Kidney
of prospective,
Study

steroid-resistant

or present

lesions

the
in

early
studies Childhood

1970s,
by

a series
the

multicenter,
of Kidney Disclinico-

other

than

MCD

(Table

1).

cooperative

International established

(ISKDC)

definitions,

Presentation Children hood

presenting girth. allergic cabby by the

pathologic became
NS (5,6,8). proteinuria

correlations, the basis

Idiopathic of 40

and
NS mg/m2th

recommendations and
defined and

for therapy
as the combination of

that of
2.5

with but
complaint

MCD rarely
edema until In extreme

generally in the
is facial the to the urine parents cases,

present
edema or

during (12).
increased

early The
as Edema

childusual
being is typitolerated ascites present an caused

for diagnosis
was

management
hypoalbuminemia

of pediatric

(5,6)

neonatal

period

abdominal

Periorbital in origin of great children. or scrotal primary entry Streptococcus

is frequently but massive Children or of these

misdiagnosed can be well with

gm/dL, 16 yr primary The

biopsies

usually of age disease ISKDC

from

with without known studies

children

edema, clinical

in a child or

between (8). groups

3 months evidence of lesions

and of a in

is examined. edema,

laboratory

concern

to cause identified
early

proteinuria several diffuse

and
distress with

pleural

effusions,
peritonitis, site).

can

produce
pain. septicemia, all

symptoms
with cellulitis infections

of
NS

respiratory
can are (without

in the course

MCD, tion
and tive category mesangiab

focal (DMP)

gbomerubosclerosis, characterized
area, membranoproliferative nephropathy hypocomplementemia and pediatric the

of idiopathic mesangiab of
(1 ,5). of of

NS, i.e., prolifera-

or labial Almost

by the finding
(MN) rarity

cells/peripheral
Because of MN the in

apparent by

gbomerubonephritis, membranoproliferaidiopathic

pneumoniae

or an enteric with
When with However, be seen occurrence steroids.

bacterium. with
to of the (except not

membranous gbomerulonephritis

The
normalities

majority
or

of children
hematuria. resolve

MCD

present

little
these steroids

accompanying

hypertension

present a response

in MCD,

or no ab(6).

typically of onset), to orally and

children, Focal
sence interstitial and which angial sometimes may far

these
of

two lesions

are now
NS.

typically

excluded

from in the
atrophy

the aband from (5,9), mes-

The
features

combination
listed

of hypertension
MCD. 1 can their in Table

and

hematuria
any in MCD does

is particularly
unfavorable possibly preclude a

idiopathic

uncharacteristic neonatal response

gbomerular
of segmental fibrosis, less ominous is generally hypercellularity seen

or focal
sclerosis was than identified (3 of greater as a focal

global

obsolescence,
tubular a pattern as

or significant recognized focal today or diffuse difficulty segmental as FSGS finding

distinct hyalinosis

administered

( I 0).
mesangial in MCD

Mild

Approach Children
hospitalized senting initiation idiopathic massive with of

to the with
to rule the NS steroid (Table

New an
out

Patient episode
(Table now 2),

cells/peripheral in early

area), or FSGS, (1)

initial

of

NS
as well

were

traditionally
preor is simple biopsy if edema complication

complications However,

or other children

conditions as for with only

be predictive

management

syndrome therapy. I ) are

but

not necessarily

an unfavorable

outcome.

hospitalized life-threatening

or if infection

or another

Minimal
Renal MCD,
patterns abnormality hypercellularity

Change
Biopsy overwhelmingly
in pediatric on light is electron seen

Disease
the
NS (5,6), microscopy; in some there

most

common
mild cases or

of
by focal

the
little

biopsy
or no

is characterized (nil-plus

Table

1. Probability
pediatric

of MCD NS

in early

biopsy

of idiopathic

mesangial disease).

Parameter
No negative correlates

Probability
90 to

(%)

Immunofluorescence
tive. On of

is negative
microscopy,

or occasionally
is epithelial

weakly
foot

posiprocess of

95

fusion
ities

in the

absence or epithelial

of immune
basement

complexes,
membranes, or

other

abnormal-

Random Female Child >6

Hypertension of

case yr old
alone

90 70 65
60

gbomerular

proliferation

endothelial The
with the age

cells
of the

(1). children
disease.

proportion
at the

of nephrotic
onset

who
The

have
great

MCD
majority

varies MCD in older

nephrotic (80 children Although

remission, less Based common on

children (5,6).

between The

the ages frequency

of 1 and of MCD

6 yr have is lower

Hematuria Infant (3 Postpubertal

Prednisone

alone months
resistant1

to 1 yr)

50 20 20
20

to 95%)

(65%) (6) and still lower in adults ( 20%) (1 1). the great majority of children with MCD respond to of oral
in the children

Hematuria Infant (<3

references
a

plus

hypertension
5, 6, 1 1, and or 40 mg/rn2 12. daily for I month,

10 0 to 5
then 3 of 7

1 to 2 months

steroid
to this with of MCD

therapy
course other and of

by
oral biopsy extensive

entering
steroids patterns

complete
alone are (5,6).
b

months)

responses frequency

From Dose for

of 2 mg/kg 1 month.

clinico-patho-

days

826

Journal

of the American

Society

of Nephrobogy

Table

2. Evaluation

of child

at the onset
Test

of the NS
Condition Considered

Diagnostic

Chemistry
Antistreptococcal

panel
titers

NS, (C3, C4, and CH-50)

renal

failure
(rarely a simple NS)

PSAGN

Serum

complement

MPGN,

SLE.

PSAGN nephritis with nephritic features)

Hepatitis Antinuclear Renal Tuberculosis

I

B surface antigen or anti-DNA antibodies skin test acute gbomerubonephritis; MPGN.

Hepatitis B-associated SLE (older children

ultrasound

Renal vein thrombosis (infants) Risk of activation by steroid therapy membranoproliferative gbomerubonephritis; SLE.
systemic lupus

PSAGN.

poststreptococcal

erythematosus.

is

suspected. and

Otherwise, steroid relapses therapy are

diagnostic are begun common

studies, in MCD,

tuberculin home testing

skin setting. for to or chilof

in the

episode sion. The

of NS, incidence

patients

were

more after

likely 1 yr was

to remain 36% after

in remisthe bong

testing. Although

in an outpatient

of relapse

proteinuria allows detection and treatment of most recurrences before gross edema develops. Most parents can be taught test other dren zoster
physicians

course, 6 1 % after short course. The steroids the compared therapy course the long The
sive NS years, courses

the standard treatment, improved outcome with for at least 2 yr. There when the different

and 8 1 % with the long course was no difference therapies

the of in were

persisted

the

urine and

for

protein, the

initiate features steroid require With

steroid therapy, prompt

can

therapy

in simple infection

duration

of remissions

relapses,

recognize

of bacterial

complications. During exposed to chickenpox immune

and

nonimmune administration
be avoided

for treatment were comparable groups. protocol

to treat

of recurrences. Side effects in the standard-therapy of these the initial for studies, episode with
may

of steroid and longcenters and use short

As a result to treat
relapses.

many of NS

globulin.
parents,

careful

coordination

between

hospitalization

great

majority

of cases.

long-term is very
commonly

prognosis
good. until However, puberty

children
relapses (15).

steroid-responoccur number for many of chil-

Treatment

A small

Steroids. Steroid-responsiveness ISKDC (8) as a total remission at least three weeks of 60

of NS was defined by the (proteinuria of 4 mg/m2h in within 1 week) within mg) of daily prednisone 4

dren These short may

with NS relapses

may continue to have recurrences as adults. are usually not severe and can be treated with Even though steroid throughout childhood, are not common. steroid-responsive children eioral or side therapy serious

urine samples obtained mg/m2 (maximum, 60

courses of oral prednisone. be required intermittently of steroid agents. toxicity Some

given in divided doses, followed 40 mg/m2 prednisone administered

tive daily days of 7). Some and renal most treatment now use maximum,

by no more than 4 weeks of intermittently (3 consecucenters alternate-day use 80 mg prednisone as the as

sequelbae Alkylating

intermittent are difficult

therapy. to obtain

Because in ratio
the

reliably children,

timed proteinuria

urine is

specimens generally

ther relapse frequently or require high daily doses of steroids to maintain remission. These frequently relapsing steroid-dependent children may develop significant steroid effects, including growth lenticubar cataracts, and with roids bucib
NS

quantified by the (milligram/milligram).

normal range when

of urine Proteinuria
urine

protein to urine creatinine is considered to be in the

ratio is 0.2

failure, hypertension, osteoporotic bone toxicity or acquired

posterior subdisease. Patients resistance to steor chloramremission of

the optimal

significant

steroid

proteinlcreatinine

and within

nephrotic with recently,

when MCD most

the who

ratio respond

is therapy.

( 13).

Of

the most

95%

of

typically respond with a prolonged

(16,17). There

to oral cyclophosphamide and sometimes permanent

disagreement regarding

children Until

to prednisone, regarding

do so

is some

2 to 3 weeks

of daily

of the information

the optimal

duration of alkylating being 8 to 12 weeks (maximum dose, imum

mg/kg). partially 200

agent of 2.0
or 0.15

therapy, with suggested ranges to 2.5 mg/kg cycbophosphamide maximum total cumulative mg/kg chborambucil (maxtotal cumulative dose, I2
agents cases. The may be used in of effectiveness

duration of steroid therapy dotab. A series of controlled

in children with trials comparing

MCD was anecthree protocols this issue the drug they then

single
mg/kg)

dose, 6 mg;
courses

100 mg;
to 0.20 maximum
of alkylating

for the administration of oral prednisone has clarified (14). Patients receiving the short course received daily until their urine was protein-free for 3 days; received alternate-day levels became normal 4 weeks of daily

single

dose,

Second

or previously

responsive

prednisone until their serum albumin (mean, 16 days). Standard therapy was followed by 4 weeks of alternateof prednisone involved 6 by 6 weeks of alternate-day was used to treat the initial

alkylating
tration

agent

therapy

is enhanced
prednisone.

by concomitant

adminis-

of alternate-day

prednisone

day therapy. The long course weeks of daily therapy followed treatment. When the long course

At Some white and

these doses, oral alkylating children (5 to 10%) develop blood cell counts agent are measured the alkylating

agents are well tolerated. mild leukopenia. Therefore, weekly withheld during treatment or its dosage

is temporarily

Treatment

of NS

827

reduced mm3 noted during ticeable

phamide

in patients or neutrophil greater-than-usual a course abopecia

can intake cause to

with count

a white of amounts

blood of hair

cell

count

of families

4000/ have comb

its

pediatric

counterpart. in and Relapses older remissions occur, adults

Hypertension

and

acute

renal adults

failure with

2000/mm3.

Some

at the onset
particularly

of the NS occur to steroid

more
(20).

commonly
Although

than
most

in children, appears
in appears children to be

on the childs

of treatment is uncommon.
acute limit patients

with cycbophosphamide, but noThe metabolites of cycbophoschemical in the cystitis, requiring

MCD
be less (20,22).

respond

therapy.
slower but steroid

the response
to develop dependency

rate
than

to

lower

or chronic concentrations receiving

that
fluid

this

medication

be given

in the morning
chlorambucil

with
urinary

a large
may

daily

common azathioprine
producing

in adults. (22),
more ( 5.5

Alkylating have
prolonged daily

agents

(20,22), effect
12 months)

and possibly with

of

bladder. develop

even
roids,

an additive
for or adult patients

corticosteproteinuria. may also MCD, be

Occasionally,

remissions

seizures, dren ing with agents. There

and cycbophosphamide a history is concern Sterility of convulsions. regarding has been

is therefore the long-term reported

preferred effects in patients

for chilof alkybattreated courses in boys as (1). and

less

Cyclosporine
effective

mg/kg
steroid-resistant

in adult

steroid-dependent

with
nosis the

limited
mortality

risk
rate

of nephrotoxicity
treated in older

(25).
MCD with

The
NS

bong-term
good, exceeds

progbut actuarial

in successfully

is generally

children, particularly with prolonged The incidence of sterility is as high

increases with repeated because usage. the Girls cumulative

or repeated as 15 to 20%
appear doses to be have

expectations

for age

(20).

much been

affected.
in recent

The
years

risk of sterility

is dose-dependent

and may

be less
lim-

Focal
Renal sion

Segmental
Biopsy

Glomerulosclerosis
of children
with prednisone. FSGS reveals

ited. been

Treatment associated there

occur used

of other conditions with an increased are

for

with alkylating incidence of that

the must be receive limited

agents has neoplasms. mawith alkylating

A small
when halfofthese

percentage
treated children

with
The (5,6).

NS do not enter
biopsy Although in more

remisthan

Although
lignancies regimens

no data
NS, the

demonstrating
who possibility

secondary
discussed

uncommon

in children

compared
gbomerular

with
disease

MCD, among

FSGS

is the
and

most

frequent
only

progressive
to congen-

in childhood

is second

the

families

and

the children Alkylating with MCD; Simple agent

mg/kg

(if they agents however,

are old enough). are when that

are risk of

ital anomalies The merubi

rosis earlier visceral epithebial

the causes

of pediatric

ESRD

(26).

Cycbosporine. needed in patients usually well mg/m2 and

many

not commonly needed, they are do not respond ( 200

transient

pathologic diagnosis of FSGS is made have segmental capillary collapse and

on light changes, epithelial cells microscopy. but cell from these the podocytes, basal Electron are not lamina microscopy specific duplication of the for

when any gbmesangiab sclemay FSGS: separation baseand reveal loss of of

effective. to an alkylating or dependence

nephrologists 5.5

cases may
daily), but the

of MCD respond
responses

to cycbosporine
often

on cycbosporine
prefer

is common
limited

( I 8).

However,

gbomerubar

cycbosporine

ment

membrane, features

and epithelial and variants

degeneration of FSGS,

or necrosis. recently

Other reviewed

nephrotoxicity chronic steroid course

in pediatric MCD (19) to the therapy or the risk of sterility agent.

side effects of from a second

pathologic

of an alkylating
in Adults

elsewhere (10), are not included Rich (3) described a pattern

analysis of autopsy before material the was the NS, many

in the present discussion. of evolution in a retrospective

from 1 8 children era. In who those only died who with had

MCD
with

antibiotic

Comparison
those definitions, pediatrics

of the major
in children criteria and internal for may biopsy,

patterns
be and

of idiopathic
by treatment The prevailing regimens

NS in adults
differences between often dogma, in

developed
agnosis sion
tern

fatal
of the

acute
NS, FSGS generally

infections,
absent > 1 yr

mostly who
after

within
seen

1 yr after with Although hypertenhad

di-

complicated

or was

in some more

juxtamedubbary
or uremia,

gbomeruli. and total

Children

died
diagnosis,

medicine.

supported that MCD by massive

steroids, pathic NS,

only

by discussions

between

colleagues,

has

been to

widespread
study. conclusions. the

gbomerubar from
source

obliteration. MCD
of the

a patby this
firm

in children is more frequent, more often complicated edema and bacterial infections, more responsive
and more likely to relapse than that in adults.

of evolution

of FSGS

was
cases

suggested
precluded

postmortem

In a large

series
White

of early
ci a!. (6)

biopsies
found

from
MCD

children
in 88%

with

idio-

Churg

and

White

and

associates

(5,6)

reported

that

children of NS resisto of

of unselected

and 64% of referral cases; the difference was probably influenced by the practice of pediatricians not to refer uncomplicated, ment
24)

with FSGS in biopsies obtained at the time of diagnosis showed a clinical pattern of initial or rapidly developing tance renal
cases years Because

steroid-responsive NS (presumed MCD) to renal treatcenters. Because NS in adults is not easily treated (20and because MCD is less frequent as a cause of NS in than
been the and

to steroid therapy, commonly followed by progression failure. Other investigators (15,27) described a number
with evolution FSGS whether can to resistant NS be these missed FSGS and/or in a needle and ESRD biopsy, after many MCD. particularly of steroid-responsive biopsy-diagnosed

adults
long as regarding 20%

in children
the standard frequency apparently

( 1 1,20),
practice of MCD decreasing

early

renal

biopsy
medicine. adults,

in NS
The reported

has
data more

in internal in nephrotic as

when
uncertain

juxtamedublary separate indicators

can

glomerubi
patterns

are
of

not
early

sampled,
and

it remains
late FSGS

FSGS

becomes

common In certain

( I I ,20), respects,

are therefore adult MCD

probably is more

reliable. difficult to treat than

represent specific
this

entities or the extremes of cause or classification

be resolved.

of one process. are needed

More before

question

828

Journal

of the

American

Society

of Nephrobogy

Treatment

Table

3.

Intravenous

M-P M-P

pulse

regimen No. Prednisone

Steroids
found Gubler
diatric

and
reported
In

alkylating

agents.
responsive
studies of

Although
to prednisone.

the

ISKDC and in pe-

FSGS (28)
FSGS.

to be poorly
further

Habib
of intermittent

Week

20 to 25% agent.

steroid-responsiveness
the effects

I to 2
3 to 1 1 to

30 mg/kg 30 mg/kg
30 mg/kg I8

3 times/wk every
every

10

1 wk
2 wk

6 8
4 with

none 2 mg/kg qodh

or without taper

prednisone

plus

a cytotoxic

compared

with

prednisone

alone, the ISKDC reported no added benefit from azathioprine (60 mg/m2-day for 90 days) (8) or cycbophosphamide ( 2.5 mg/kg body weight daily for 90 days) (29,30) in the treatment of steroid-resistant phosphamide had the renal already using early treatment with with noted them, FSGS. The ISKDC no robe in the treatment of this abandoned of success, concluded of FSGS (29,3 that cycbo(29). After 1 ), many therapy others and and late continued forms of had

19 to 50 5 1 to 82
a
I)

30 mg/kg 30 mg/kg
dose,

every every
1,000 mg.

4 wk 8 wk

8 4

slow slow

taper taper

Maximum

Maximum

dose,

60 rng; qod. every

other

day.

presentations centers a benefit some

interpretation immunosuppressive FSGS. However, agents

for children

steroid-resistant

courses slowly.

of treatment White in cases blood

were cell

used counts

in patients were

who measured

responded weekly,

more and

alkylating

in the early

the

alkylating

agent

was

temporarily

withheld

or

its dosage

the disease (28,32-34). Cycbosporine. Because pressive agent in solid-organ cycbosporine has been widely

reduced

of leukopenia.

of its efficacy and bone evaluated

as an immunosup-

marrow transplantation, in a variety of immu-

If the alkylating weeks of the M-P

agent protocol,

was started at the end of the first 2 pulses were given weekly until the

nobogicalby mediated diseases. In pediatric NS, a consensus has emerged that cycbosporine is more effective in steroid-dependent than steroid-resistant disease, that the efficacy of corticosteroids is a more cyclosporine than important determinant is the renal biopsy. of responsiveness to and that there is a high (35,36). in steroid-

end of the alkylating therapy and then continued as in Table 3. If the alkylating agent was needed later, six pulses were repeated over 2 weeks and then the alkylating agent was given
with weekly pulses. When a patient showed a partial or com-

plete

response

to this agent during

ratio administered.

M-P/tripbe-therapy

protocol

(M-P

pulse

rate of relapse after discontinuation of cycbosporine Moreover, cycbosporine may be more nephrotoxic resistant than with bow-dose ness in steroid-responsive or alternate-day in producing disease (35). steroids increases sustained

plus alkylating either relapsed

protein/creatinine agent was

plus alternate-day prednisone) and then the protocol or failed to achieve a urine
of In

1 .0, a second
most cases, protocol,

course
the were

of alkylating
second course

Combined use the effectiveof probut 20

200

produced
occurring

a more
after

complete
completion

and
of

stable
the

response. with standard

Late

relapses,
as if

of cycbosporine

reductions

treated

teinuria in steroid-resistant disease, including FSGS (36), this effect has not been seen in all studies (37). The French Society of Pediatric Nephrobogy (36) treated
cases of steroid-resistant cycbosporine FSGS combined with 6 to with 12 months of mg/m2-day

they nisone

were

new

cases and

of NS, advancing

starting to M-P without

daily

predtherapy protein-

therapy

pulse with most

or triple abnormal recent

only as needed. The numbers uria and decreased (38) examination complete patients

of patients renal are shown

and on

30 mg/m2 day.

prednisone 3 yr of com-

function

follow-up were in of these but re-

daily plete erate ESRD,

for

1 month results

and were

then

every

other complete

After or nearly

in Table

4. Two-thirds

follow-up,

as follows:

remissions proteinuria, 30%;

(proteinuria of < 10 mglkgday), 35%; mod5%; nephrotic-range proteinuria without ESRD, 30%.

remission and receiving no therapy. Four had relapsed after completing the protocol

Methylprednisobone/triple-therapy
est rates of remission in steroid-resistant been achieved prednisobone an alkylating
is detailed

protocol.
FSGS

The

highhave

Table

4.

M-P

pulse/triple-therapy and FSGS renal

protocol: function

effects

on

in children

proteinuria pediatric

in steroid-resistant

with a regimen combining a series of methyl(M-P) pulses with alternate-day prednisone and agent ( I 3,38). The M-P pulse/prednisone regimen in Table 3. An alkylating proteinuria using had agent not been was fully added in 78% by proby 2 (1)

No.

Remission, Proteinuria urine

normal protein!creatinine

Cr Cl ratio ratio
> >

21/32
0.2 0.5 to 0.5 to 2.0 1 .9 3/32 2/32 6/32

66
9 6 19

of cases, M-P teinuria istered weeks plus

in which prednisone,

controlled pulses
response

the following

indications:
or partial

not significantly improved over 2 weeks; (2) a complete with a subsequent significant

by six M-P increase

adminat

urine protein!creatinine nephrotic protein/creatinine Renal function normal Cr Cl proteinuria, decreased ESRD
a

ratio

of proteinuria

any time during the M-P regimen; and (3) a urine protein! creatinine concentration ratio of 2 at week 10 or later. The alkylating agent, chosen at the discretion of the individual nephrobogist, was either cycbophosphamide (2.0 to 2.5 mg/ kgday) or chborambucib (0. 1 8 to 0.22 mg/kg-day) (based on lean nonedematous body weight) for 8 to 1 2 weeks. The longer

Cr Cl

3/32 5/32 3/32 calculated

Data and

9 16 9

Cr Cl, creatinine
80 38.

clearance,
m2).

from
methods

serum

creatinine

(normal, reference

mL/rnirnl.73

are from

Treatment

of

NS

829

sponded

to retreatment

(three

with

M-P

plus

prednisone

and

authors M-P/triple FSGS

(>50

experience therapy

in the (13).

prepubertal

children

treated

with

one had
serum all most 0.02

with normal

triple blood

therapy).
therapy

Although
during the

several
protocol,

children
all

required
responders

antihypertensive

pressures,
concentrations,

without
were

antihypertensive
clearances. 80 ratios was estimated mL/min-l.73

agents,
from m2 in

in Adults
a higher
has adults. than children prolonged

in follow-up creatinine recent

monitoring.

Creatinine

Although

frequency
been The for

of nephrotic-range
reported in children

proteinuria
with FSGS

mg/kg-day) and FSGS groups and to

2 1 patients (mean with

All

without
urine
SE),

abnormal
serum was albumin 1 22

proteinuria.
4. 1

In these
averaged 0.2 g/dL,

2 1 the
0.06 and

(2 1 ), the prognosis
in children nephrotic both both age adults

and response
outcome

to therapy
is poorer

of FSGS
for nephrotic

are similar
unresponsive disease FSGS potential of therapy in in for

protein!creatinine

non-nephrotic Nevertheless, has or a newly aggressive

or responsive recognized courses

creatinine

clearance

6 mL/minalso renal ratio had failure

protein/creatinine

1 .73 normal

m2.
ratios

Three
re-

(2 1 ,38,44).

children
clearance.

persistent
six patients

proteinuria
whose

creatinine as did

responding

mained one with one group with

2.0

developed

chronic

or ESRD,

(38,45).
The FSGS
correlate 8 months steroid-induced

a urine a ratio

protein/creatinine of 1.1 (after

of disease the protocol

of 0.4 (after
few and mild,

1 2 yr) and
as were in a

recent treated
with

increase with
increased

in complete oral steroids

duration

remissions (to 30
of treatment,

in adults appears
with were appeared often

with to
S to less to studies

5.3 yr).
were effects

to 60%) patients
relapses

Complications

of children

given

more
(39).

aggressive
Side

M-P
of the

pulse
steroids

therapy

for
no

of daily in adults
or the number

therapy
remissions

(45).
in

Among
one study,

who

achieved of cycbo-

rheumatobogic

greater than those steroid-dependent limited Perhaps of the

long

seen with prednisone MCD, and alkylating cases toxicity of mild is limited
pulses.

therapy of relapsing agent toxicity beukopenia protocol and

or was (40).

frequent
phosphamide increase

than

in children
of responses

(2 1 ). The
regimens (45), has but

addition
not controlled

chborambucil

to a few steroid avoidance

intervals

and

transient

in the M-P

because the

have
studies

not
in

been
this

done
analysis in adults with

and
with than FSGS racial

the
were

steroid
not nephrotic

regimens
standardized. FSGS of (25). has efficacy

in the
The proved and

several
use a much of to be

of daily
between

prednisone Other groups

administration have FSGS

in four

cycbosporine

Other
M-P Table between and
therapy response gland completed. agents. (42)

M-P
5 shows

protocols. for
a direct

used
reported

modified ( 13,41,42).
series,

problematic, higher risk

a lower

likelihood in MCD has Black groups been adults

pulse the

regimens percentage
requires

steroid-resistant
relationship,

of toxicity

The
ness adults in than

influence
to therapy than adults

of race
of

on the natural

history
with NS FSGS

and
in greater are (46).

responsivedetail more likely Although in

of children of successful
the addition or recurrent rapidly both two with cases, less

given outcomes.
heavy before failure

an alkylating The

agent
agent One child

studied to have

the

percentage
protocol to persistent died Except which also

M-P/triple-

in children. in other

of an alkylating proteinuria. (4 1 ) and

black
overall larly

patients
prognosis resistant

with
and

FSGS
(24), progressive

do

not
variant

necessarily
gbomerulopathy, of FSGS,

have

a poorer
a particumore

in Birmingham

deteriorated of septicemia, in those correlated

one
to use

in New
could alkylating M-P

Enbe

collapsing

treatment

is much

aggressive

therapy,

common among black patients In any analysis of response

outcomes in adults with those FSGS

than white patients (47). to treatment, comparisons

in children may not be valid.

of to ste-

represented The with Table

(13). and children

a deviation results of therapy different majority

FSGS other racial

from

the protocol. nephrotic FSGS in children in these

reported among black (43), this

of steroid-resistant regimens of children

Because
roid-resistant

the

major
nephrotic

pediatric may be

studies
(by

have
ISKDC

been cases

limited with

several 6. The
Although more

are compared in studies were white

aggressive than not among been the children has

criteria),

pediatric

and

adult

series histories

composed levels

of

different to therapy

has

been groups

to be more

treatment
(30,36,38).

and different

of resistance

resistant of

to therapy

Diffuse
DMP
Table 5.

Mesangial
is an uncommon
there predominantly

Proliferation
biopsy
is mesangial for 1gM,

pattern

in pediatric is either

NS negative
no

(5,6). or

Treatment M-P pulses:

of steroid-resistant use of alkylating

%

pediatric agent

FSGS therapy

with

Pathologically,

proliferation and there

in all gbomeruli are immune

on light
positive

microscopy, on
sections, classified may be was more

immunofluorescence microscopy. cell

been as response much variations more

of Patients Total Failures (NS, CRF, ESRD)

.

complexes characterized
2-j.tm mesangial otherwise disease) has (5,6),

electron by >3
has

Mesangial per mesangial

from focal area)

proliferation, stalk
or

Study

Alkybating Agent Used

nuclei

on

I- to

distinguished (3 cells/mesangial MCD

diffuse

Los
New

Angeles
England

(13)
(38) (42) (41)

100
78 53 20 failure.

18
25 47 100

hypercellubarity

in biopsies

Stanford/UCSD Birmingham
a h

( 1 ). The
to control therapy. resistant

latter
than As

pattern MCD

(nil-plus but often

described than MCD

difficult to

a favorable DMP

originally steroids

to oral studies

CRF.

chronic

renal

UCSD,

University

of California,

San Diego.

but
been

usually
significant

resolved

whether
among

treated

or not

(6).

There
NS

have
in the

of pediatric

830

Journal

of the American

Society

of Nephrobogy

Table

6. Treatment
prednisone,

of pediatric
and the

steroid-resistant
M-P/tripbe-therapy

FSGS:
protocola

natural

history

and

the effects

of cyclophosphamide,

cycbosporine/

No. of Patients

Responses Complete Partial

.

(%)h

Failure

Standard Churg White control:

prednisone ci al. (ISKDC) et a!. (6) 1 year (5) (30) 21 32 20 32 persistent after 1 month of daily, followed 28 25 35 66 by I month 28 25 5 9 of intermittent (3 of 7 days 43 50 60 25
or

10 10

0 0

100
100

Cycbophosphamide cycbophosphamide Cycbosporine/prednisone M-P/triple

a

(ISKDC) of prednisonec
+

prednisoned (36)

therapy defined

(38)e as proteinuria

Steroid

resistance

alternate-day), oral prednisone or prednisobone, except in the cycbosporine study, which used I month of daily prednisone followed by iv M-P (3 X I g/rn2 over 1 wk). Follow-up: ISKDC cycbophosphamide study, 3 to 102 months (average. 42 to 45 months); M-P/triple therapy, 9 to 150 months (average, 76 months); cycbosporine, 28 to 58 months (average, 38 months). b Complete response proteinuria: ISKDC and White et a!., 4 mg/m2h; M-P/tripbe therapy. urine protein/creatinine ratio 0.2; cycbosporine. < 10 mglkgday. Partial response: ISKDC, abnormal but a decrease of at least one of four categories of proteinuria (<4, 4 to 40, 41 to 100, and >100 mg/rn2th); M-P/tripbe therapy. urine protein/creatinine ratio > 0.2 to 0.5; cyclosporine. proteinuria of 10 to 50

mg/kgday. Failure: persistent NS or ESRD. C One year of alternate-day prednisone (40 mg/rn2). d One year of alternate-day prednisone (40 mg/rn2) plus 90 days C Complete plus partial responses (75%) with M-P/triple therapy

of cycbophosphamide (2.5 mg/kgday). are comparable to complete responses

(35%)

with

cycbosporine.

reported
possibly

frequency
because

and
of the

resistance
criteria used

to therapy
to establish

of DMP
the

(6,48), but have of that

of treatment-resistant
rotic report suggests disease of and lowering A a potentially of

NS
deterioration

may

contribute
of renal lipids inhibitor approach by in

to later
function.

atheroscle-

diagnosis.

A preliminary NS long-term

The

authors NS.

have The

not that

seen

many that

cases have

of true been treated

DMP

plasma valuable

a hydroxymethylglusteroid-resistant to this

not been pediatric

impressed

it is a spontaneously in the treatment

resolving

form

taryl-coenzyme

reductase

few cases is effective

suggest

M-P/triple therapy from DMP.

of NS resulting

complication

(50).

Summary Other
The effective

Therapies
angiotensin-converting antihypertensive enzyme agents for inhibitors (ACEI) patients with NS are
who

This responses in children

review and

compares and adults. On

the first

biopsy

patterns, outcomes

complications, of idiopathic distinctions NS be-

to therapy,

long-term

examination,

develop blood pressure elevation either from renal disease or from steroid therapy. Moreover, FSGS therapy slower ACEI of these
namic

their primary patients with

tween than
cence,

the pediatric absolute.

can

and

adult

diseases growth,

seem

more

quantitative of outcome, and senes-

However,
present very

underlying
different

determinants maturity,
for challenges

that

is incompletely decreased of renal must

of

responsive

to immunosuppressive

including and

immunocompetence,

may have deterioration (49). Caution antihypertensive

compromise

proteinuria and benefit from function when treated with an when is begun,
by

pediatricians

internists. major biopsy patterns in pediatric and DMP. MCD is overwhelmingly steroid-responsive
of massive

be used agents
renal

administration to avoid
vigorous

of one hemodyACEI or

The FSGS, and

sents

NS include MCD, the most frequent but prompt commonly

infections,

function

most multiple

of the
edema.

three
serious

preof 1

combined ACEI/diuretic therapy. Thromboembobic disease is a relatively dangerous, not been complication systematically

problems

bacterial

uncommon,

but very

and

relapses.

Because

of

the

response

of the NS. Preventive strategies have studied, but the authors use the fobavoidance of aggressive diuretic ther-

pediatric MCD to corticosteroids, steroid has generally been defined as persistence month of daily followed by 1 month administration. steroid-resistant
therapy, steroid-resistant typically but

resistance in children of proteinuria after prednisone is usually aggressive

commonly to what clear

lowing precautions: (I) apy, particularly when soon produce remission intravenous albumin hemoconcentration (3) the use of

of intermittent FSGS more

is

an immunosuppressive of the NS; (2) the or correct

regimen
concomitant

may
use of

By this criterion, nephrotic and, if not controlled by

progresses may slowly to ESRD. resolve.

to prevent

hypovolem a is necessary; patients with

and and NS

DMP It is not

when aggressive diuresis small doses of aspirin for

extent steroids showing

remissions or would a few

of have globally

DMP

represent without

a delayed treatment. glomeruli

response Biopsies mesanor mild

to

complicated by hemoconcentration The chronic hypertriglyceridemia

and/or thrombocytosis. and hypercholesterolemia

occurred obsolescent

Treatment

of NS

831

gial

hypercellularity

may

be

associated

with

greater

difficulty

7.

Coldbeck

IH: Experience

with alkylating

agents

in the treatment

innianaiicnicntllt li VC bccnillC1lldC intlicbroadcatc oryof

MCD. Moreover.
able
sion in the of some three cases

of hil r n ithtti n phroti yfltI[Ofl1 ;IIfrI(( ff:11r

1963 8. Abramowicz yashi Tiddens nephrotic 9. 10. Habib 1973 DAgati Haas year 1 2. U, HA: R: Focal V: The M, Spargo M, Barnett Arneil syndrome. GC, Controlled Lancet glomerular many BH, masks Coventry HL, Barron trial Edelrnann BA, CM Gordillo 1970 Kidney segmental tnt 4: 355-361, Jr. Greifer PG. in children I, KobaN, with Hallman of azathioprine 1 : 959-961, sclerosis. of focal 1994 5: Increasing among adult incidence nephropathies: of focalA 20-

evolution
of MCD

of patterns
of FSGS
to ESRD

in serial
and
suggest

biopsies.

van-

steroid-responsiveness major categories.

DMP,

and

progresfeatures

common

Among adults with idiopathic quent biopsy pattern, followed

dren) and then by MCD. In contrast

NS, FSGS is the most freby MN (which is rare in chilto its pediatric counterpart,

gbomeruboscle-

MCD with
likely

in adults hypertension to relapse less

this lesion.

is less
and

regularly
elderly

and failure. severe

children

more

slowly
commonly

responsive
associated

to
I 1.

rosis. Kidney segmental

mt 46:

1223-1241,

corticosteroids

in the

is more

and once

renal with

MCD edema
and

in adults Adults than

adults

is less FSGS children

FSGS

glomerubosclerosis

remission

is achieved.

with do
with

present
with

commonly
Although

study. Am J Kidney Dis 26: 740-750, 1995 Sibley RK, Mahan I, Mauer M, Vernier RL: A clinicopathobogic study of forty-eight infants with nephrotic syndrome. Kidney in!
1985

renal

biopsy

present renal
by

similar function,

challenges the more

preclude strict of DMP and in children

of resistance aggressive
comparisons in adults.

to therapy oral steroid

between

and regimens
pediatric

loss

of
and

27: 544-552,

used a
with of

13.

Tune

BM,

Lieberman

E,

Mendoza

SA:

Steroid-resistant A treatable nephrotic studies.

nedisease.

internists

phrotic focal segmental gbornerubosclerosis: Pediatr Nephro! 10: 772-778, 1996 14. Brodehl Lessons Siegel follow-up I: The treatment ofminimal learned from mubticentre 1991 NJ, change co-operative

adult
systematic

series.

There
analysis agents

is insufficient
cycbosponine and

information
have with been

to

support
used cases

syndrome:

Eur J PeLong-term
syndrome. in

Cytotoxic varying NS. success In MCD,

diatr 150: 380-387, 15.

adults

difficult

Goldberg
of children

B, Krassner
with 1972

LS, Hayslett

IP:

an alkylating of remission. but continued

agent

can treatment control

increase can of

the also

likelihood improve needed to

16.

steroid-resistant trial

nephrotic

and control

duration

Cycbosponine

J Pediatr 81: 251-258, Barratt Lancet 17. Grupe 746-749. 18. 19. Niaudet nephrosis. Gregory
RP.

in MCD, remission. has agent steroid sustained is more than not been

is often courses

TM,

Soothill

IF: Controlled relapsing 1970 SP, Ingelfinger nephrotic nephrotic

of cycbophospharnide syndrome of childhood. treatment J Med

maintain FSGS bating tent more

icity

Significant achieved
especially

steroid-resistant of an alkyof these

intermitwith

steroid-sensitive 2: 479-482, WE, Makker

with Longer

limited courses

or cycbosponine. administration,

of either complete

IR: syndrome.

Chborambucib N Eng!

immunosuppressants,

when

combined

of frequently

relapsing 1976

295:

can

produce

more

and/or

P. Habib

R: Cycbosporine Soc Nep/iro! WE, TE: Sedman

in the treatment 5: 1049-1056, A, Kershaw A clinical

1996

of idiopathic DB, histologic Valentini therapy anal-

remissions. However, severe in FSGS than in steroid-dependent

cycbosponine in MCD and NS, regardless

nephrotoxin steroidof biopsy

J Am
MI.

1994 cycbosporine and

Smoyer nephrotic

resistant

Johnson

K, Bunchrnan

Long-term

pattern. A protocol combining prednisone, and an alkylating nc mens. tocols FSGS has
with

iv M-P pulses, alternate-day agent in steroid-resistant pediathighest

function,

of pediatric
ysis.

syndrome:

J A,n Soc Nephrol

7: 543-549,

produced
normal

the
renal

percentage
of all

of
reported

sustained
regi-

20.

remissions

DO:

Nolasco F, Cameron IS, Heywood Adult-onset minimal change

EF, Hicks nephrotic

I, Ogg C, Williams syndrome: A longP: Evifocal reg-

Controlled are needed

trials

of this

and and

other adults.

combined-drug

pro-

in children

21.

term follow-up. Pei Y, Cattran dence segmental istry suggesting study. A, segmental

Kidney mt 29: 1215-1223, 1986 D, Delmore T, Katz A, Lang A, Rance under-treatment

82: 938-944,

in adults Regional
1987

with

idiopathic

gbomerubosclerosis: A,n J Med Simon syndrome P: Treatment in the

gbomerulonephritis

References
I. Nash change and edited 2. 3. MA, focal by Edelmann gbornerular Edelmann CM syndrome, sclerosis. CM Jr. Jr. Bernstein diffuse In: Boston, I, Bamett mesangial Pediatric Little, HL: Kidney Brown, Minimal Disease, and Co., 23. 22. nephrotic hypercellularity,

Meyrier nephrotic focal I988

of corticoresistant
Minimal Ads change Nephro! 17:

idiopathic
disease and 127-150, 0, Pontion the with

adult:

gbornerulosclerosis.

1992. pp 1267-1290 Dorhout Mees El: Edema Contrib Nephrol 43: Rich AR: A hitherto ullary gbornerubi 100: 173-186, 1957

formation

in the nephrotic

syndrome.

Banfi G, Moriggi M, Sabadini E, Fellin 0, DArnico celli C: The impact of prolonged immunosuppression outcome of idiopathic syndrome focal-segmental in adults: A 1991 36: 53-59, in adults: J Kidney L-H, Dis Auriche A treatment 1446-1456, Recurrence gbomeruboscberosis collaborative nephrotic

64-75. 1984 undescribed vulnerability nephrosis. Bull Johns

of the juxtarnedHopkins Hosp 24.

retrospective

in lipoid

study. C/in Nephrol

Rydel

II, Korbet
sclerosis Am A, Noel Kidney A, Stablein

SM, Borok

RZ, Schwartz
Presentation, 25: 534-542, P, Cablard in adult

MM: Focal
course, 1995 and

segmental
response renal nephrotic glornerNorth

4.

Cornfeld children 1966

D, Schwartz treated with

MW:

Nephrosis:

corticosteroids.

A long-term J Pediatr 68: of the

1970

study
507-515,

of
25.

glomerular to treatment. Meyrier tolerance syndrome.

P: Long-term idiopathic segmental report of the

5. 6.

Churg
syndrome White nephrotic

I. Habib
RHR,

R, White
Lancet

RHR:

Pathology

nephrotic
study 1970 of 26.

of cycbosporin DH:

in children. Glasgow syndrome

I: 1299-1302, Ltincet

ira 45:

1994 of focal

EF, Mills in childhood.

RI: Clinicopathobogical 1: 1353-1359,

Tejani

ubosclerosis

posttranspbantation:

A special

832

Journal

of the American

Society

of Nephrology

American 27.

Pediatric 2[Suppl of

Renal

Transplant

Cooperative 1992.

Study.

J Am
39. 40.

tal gbomerubosclerosis:
84-88, 1995 II: Prolonged diseases SA. Reznik with Miller rheumatic Mendoza

A bong-term
use VM, of large Griswold

follow-up.
intravenous WR,

C/in steroid

Nephrol pulses 1980 AM,

43: in

Soc Nephrol

3]: 258-263,

Hayslett

JP. Krassner

LS, Bensch

KG, Kashgarian
to renal

M, Epstein
insufficiency.

FH: Progression NEnglJMed28l: 28.

lipoid nephrosis 181-187. 1969

of children.

Pediatrics

65: 989-994, Krensky

Yorgin

Habib R, Oubler MC: syndromes ndphrotiques

382-401, 1971 Study International

Les lesions idiopathiques

Disease

gbom#{233}rulaires focales de lenfant. Nephron

in Childhood: Cycbophos-

des
8: 41.

PD,
agents.

Tune

BM:

Treatment
pulse

of steroid-resistant
methybprednisobone 1990 EC: 4: 303-307, Kohaut

focal

segmental

gbomerubosclerosis

and alkylating treat-

Pediatr
FB, of patients

Nephrol
MR, with

29.

of Kidney

Waldo ment

Benfield

Methylprednisobone nephrotic syndrome.

phamide
controlled

therapy
clinical

30.

Tarshish
phamide uboscberosis: ease

P. Tobin
does

segmental glomerubar sclerosis: A trial [Abstract]. EurJ Pediatr 140: 149, 1983. JM, Bernstein I, Edelman CM Jr: Cycbophospatients with focal segmental gbomerDisof the International Study of Kidney

in focal

steroid-resistant

Pe-

diatr Nephrol 42. Guilbot the 43. stract]. Ingulbi outcome 44. children. Cameron long-term loscberosis. 45. course

6: 503-505, 1992 AP, Kim MS: Pulse steroid

of focal segmental Soc Nephro/ A: Racial idiopathic 4: 276, differences focal

therapy
1993.

(pst)

does

not alter
lAbrenal in DO: The

not benefit A report

glomerubosclerosis in the incidence

(FSGS) and

J Am
of

31.

in Childhood. Pediatr Nephro! 10: 590-593, 1996 Spitzer A, Gordilbo-P 0, Houston IB, Travis LB: Prospective, controlled trial of cycbophosphamide therapy in children with the nephrotic syndrome. Lancet I : 423-427, 1974 Siegel NJ, Kashgarian M, Spargo BH, Haysbett JP:

E, Tejani

segmental

gbornerubosclerosis

Pediatr Nephrol IS, Turner DR,

5: 393-397, 1991 Ugg CS, Chantler C. Williams focal segmental 1978 to

32.

change
33. Mongeau

and focal
1974 J-Y,

sclerotic

lesions
L, Robitaille prognosis

in lipoid

nephrosis.

Minimal Nephron M: 46.

prognosis of patients with C/in Nephrol 10: 213-218, MM, Clinical RM,

gbomerusegmental therapy. racial

13: 125-137,

Gorneille

P URegan that severe?

5, Pelletier

Korbet SM, Schwartz gbornerubosclerosis: Am

Lewis El: Prirnaryfocab course and response

1994

Primary
sclerosis: 743-746, 34. Geary

nephrosis
1981 DF, Farine

in childhood

associated

Is long-term

with focal glomerubar Kidney 1w 20:

to cycbo-

J Kidney
SM,

Dis
Genchi

23: 773-783,

Korbet prevalence ney

Borok lesions

RZ,

Schwartz

MM: adults.

The Am

of gbomerular

in nephrotic

J Kid-

M, Thorner

P. Baumal focal

R: Response segmental

phosphamide rosclerosis: 35.

in steroid-resistant a reappraisal.

gbomeruloscle-

47.

Dis 27: 647-651, 1996 Valeri A, Barisoni L, Appel GB, Siegle

focal segmental logic study. Kidney

R. DAgati
1996

V: Idiopathic
A clinicopatho-

Cliri Nephrol 22: 109-1 13, 1984 Niaudet P. Broyer M, Habib R: Treatment of idiopathic nephrotic syndrome with cycbosporin A in children. Cliii Nephrol 35:
531-536, 1991.

collapsing 48. Habib Broyer Clinical Nephro!

glornerubosclerosis: 50: 1734-1746,

mt

R, Girardin E, Gagnadoux M-F, Hinglais N, Levy M, M: Immunopathobogical findings in idiopathic nephrosis: significance
2: 402-408,

36.

Niaudet nephrosis
Mebocoton cycbosporine

P: Treatment of childhood steroid-resistant idiopathic with a combination of cyclosporine and prednisone.

1994

of glornerular
1988

immune

deposits.

Pediatr antiprotein-

J Pediatr 125: 981-986, 37. TL, Kamil A treatment Kirpekar therapy

49.

Apperboo

Al, de Zeeuw

D, de Long

PE: Short-term

dent nephrotic
38. Tune BM,

ES, Cohen AH, Fine RN: Long-term of steroid-resistant and steroid-depensyndrome. Am J Kidney Dis 18: 583-588, 1991 R, Sibley RK, Reznik VM, pediatric Griswold focal WR, segmen50.

uric response GFR decline mt 45[Suppl

to antihypertensive treatment predicts long-term in patients with non-diabetic renal disease. Kidney 45]: 174-178, 1994

Coleman
therapy

JE. Watson
in steroid-resistant

AR: Hyperlipidemia.
nephrotic 1996

diet and sirnvastatin

syndrome of childhood.

Mendoza
ing agent

SA: Intravenous

methylprednisobone

and oral alkybat-

of prednisone-resistant

PediatrNephrol

10: 171-174,