Proteinuria and the Nephrotic
Syndrome
William Primack MD
UNC Division of Nephrology and Hypertension
Octoer !" #$$%
No relevant financial disclosures
When bubbles settle on the
surface of the urine, it indicates
disease of the kidneys and that
the complaint will be protracted
Hippocrates
CASE 1
! y"o" #irl
CC$ eye swellin#
%&$ Aller#ic con'uncti(itis
)& #i(en without impro(ement
About 1 week later abdominal distension
noted and brou#ht in for further e(aluation"
*+,-!.!/ mmH#
0,12 C
)),34.min
+,-2.min
Case 1
5abs
6.A 78 protein, trace heme
micro$ 191 rbc.hpf, :91 wbc.hpf
*6; 34 m#.dl, creat :"! m#.dl
S albumin<1 #.l, cholesterol !4/ m#.dl
N&PH'O()C S*ND'OM&
+)=0E>;6)>A
H?+=A5*6@>;E@>A
H?+E)5>+>%E@>A
8.9 E%E@A
;ephrotic Syndrome in Children
C=;AE;>0A5
+)>@A)?
SEC=;%A)?
B
Systemic >llness
S5E, HS+, >%%@, obesity
B
>nfections
Hep *, CC H>D, malaria, syphilis, schistosomiasis, par(o *1-
B
Aller#y
*ee stin#s, milk, pork
B
E&posures
;SA>%Es, +enicillamine, #old, ampicillin, hea(y metals
B
5ymphomas, S9S disease
Case 1
5abs
6.A 78 protein, trace heme
micro$ bland
*6; 34 m#.dl, creat :"! m#.dl
S albumin<1 #.l, cholesterol !4/ m#.dl
C1 complement nl, A;A ne#, HbsA#
ne#, H>D ne#
;ephrotic Syndrome99Etiolo#y (s" A#e
Cameron et al+ ,m - .idney Dis /0123 /$4/52
Case 1
Clinical Course
+rednisone 3 m#.k#.day
=n day 13 of therapy, urine protein
decreased to trace9ne#ati(e with a prompt
(i#orous diuresis
;ephrotic Syndrome in Children
History 1
17/7F)oelans
B
swellin# of the whole body of the child
)&FE0ake the tops of the elder plant, and danewort,
cook in white wine and wrap the child in hot cloths
by applyin# a poulticeGand so cure him"E
1233FHwin#er
B
Associated #eneraliIed edema and kidney
122:FCotu#no
B
Associated edema and proteinuria
Adapted from: Cameron J, Ulster Med J 54:S5,1985
;ephrotic Syndrome in Children
History 3
1/32 *ri#ht and *ostock
B
Edema, proteinuria, kidney disease
1-7: >ntroduction antibiotics
1-!: Steroids first used
B
AC0H and later cortisone
1-!7 +ercutaneous renal biopsy
1-2: >SJ%C
B
Kirst prospecti(e study of treatment and
de(eloped current patholo#ical classification
;ephrotic syndrome in children
! year status in (arious eras
+re
antibiotic
+ost
antibiotic
Early
steroid
Current
Sur(i(al !1L 43L 2/L M-!L
+ersistent
proteinuria
11L 31L 74L 3:L
)emission 1/L 1-L 1-L 21L
)ncidence of Nephrosis in
Children
$+1 ne6 cases per year7/$$"$$$
%+0 ne6 cases per year7/$$"$$$
B
Children aged /80 years
%8/5 cases7/$$"$$$ ages /8/%
B
Possily more fre9uent in Southern ,sians
'othenerg et al+ Pediatrics /0523
/04!!%
+)=0E>;6)>A
+)=0E>;6)>A
37 H=6) 6)>;E
B
;ormal
<7 m#.@
3
.hr or <1:: m#.@
3
.day
<1!: m#.37 hours NadultO
B
;ephrotic ran#e
M 7: m#.@
3
.hr or M1::: m#.@
3
.day
M3 #rams.37 hours NadultO
+)=0E>;6)>A
37 H=6) 6)>;E C=55EC0>=;
B
Sources of error
incomplete.inaccurate collection
posture.e&ercise.intercurrent illness
+)=0E>;6)>A
6)>;E +)=0E>; 0= C)EA0>;>;E )A0>=
6
Prot
.6
Creat
B
normal
<:"3 m# protein.m# creatinine
B
nephrotic
M3 m# protein.m# creatinine
B
some labs report urine protein in micro#rams Nmc#O
Correlation et6een U
Prot
7U
Cr
and
9uantitative protein e:cretion
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Up7Ucr ;g7mg<
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) , "-1
n , 3:
=rthostatic proteinuria
+roteinuria present only in up9ri#ht but not
recumbent position
Kelt to be beni#n process
739!: year follow9up99no increased risk
renal disease N)ytand ;EP@ 1:!$41/,1-/1O
@easure carefully collected first mornin#
6prot.creat
Nephrotic syndrome in childhood
)nitial (herapy
# mg7kg7day prednisone
B
Controversies
Single or divided dose
Duration of initial therapy
My approach88+i+d+ for 1 6eeks
(aper
B
%$= of daily dose 9+o+d+ : ! 6eeks and
then fairly rapid taper
Nephrotic syndrome in childhood
Definitions
'emission
B
Neg or tr urine protein for > consecutive days
'elapse
B
# ? or @ urine protein for > consecutive days
Are9uent relapser ;A'NS<
B
# or more relapses in % months
Steroid dependent ;SDNS<
B
)n remission only 6hen on steroids
Primary non8responder
Nephrotic syndrome in childhood
)esponse to 7 weeks of daily steroids
>SJ%C
Nephrotic syndrome in
childhood
/$8/5= of children B /$ years 6ill e
steroid resistant
(his percentage increases 6ith age
and ,+,+ ethnicity
,out half of those 6ho respond to
steroids are A'NS or SDNS
Nephrotic Syndrome in Childhood
Complications ;if not in remission<
)nfection
B
Spontaneous acterial peritonitis
B
cellulitis
&dema
B
Supulmonic effusion" gut 6all edema
genital edema
(homosis
Hyperlipidemia
Nephrotic syndrome in
childhood
/$8/5= of children B /$ years 6ill e
steroid resistant
(his percentage increases 6ith age
and ,+,+ ethnicity
,out half of those 6ho respond to
steroids are A'NS or SDNS
Nephrotic Syndrome in Childhood
Complications of Steroid (herapy
Cehavior7sleep changes
Weight gain D distriution
ECushingoid faciesF
Striae
Gro6th arrest
Osteoporosis
Hyperglycemia
Hypertension
'isk of ulcer
Hyperlipidemia
Nephrotic Syndrome in Childhood
ESteroid SparingF Medications
)f a child 6ith A'NS7SDNS remains steroid responsive" e+g+
urine ecomes neg or tr 6ith therapy" a iopsy 6ill nearly
al6ays sho6 MCNS" indicating good prognosis+
)f unacceptale steroid side effects4
B
,lkylating drugs
Cyclophosphamide" chloramucil
B
Calcineurin inhiitors
cyclosporin" tacrolimus
B
Cell cycle inhiitors
Mycophenolate mofetil ;MMA<" immuran
Nephrotic Syndrome in Childhood
)ndications for 'enal Ciopsy
Steroid non8responsive
B
Primary or secondary
Ho6er likelihood of MCNS at onset
B
Older age" ,+,+" H(N" rc casts" lo6 C>
B
Suspicion that NS is secondary
Parental needs
B
'eticence to use steroids
B
Need to kno6 efore ;during< treatment
SSNSIHong term
Median ## y f7u
More relapsesJmore
likely adult relapse
No &S'D
'uth+ - Pediatr #$$53/!24#$#82
Nephrotic Syndrome in Childhood
Cameron et al+ ,m - .idney Dis /0123 /$4/52
ASGS
ASGS
AOC,H
AOC,H
and
and
S&GM&N(,H
S&GM&N(,H
GHOM&'UHO8
GHOM&'UHO8
SCH&'OS)S
SCH&'OS)S
+art of #lomerulus
+art of #lomerulus
dama#ed
dama#ed
Some #lomeruli
Some #lomeruli
in(ol(ed, others
in(ol(ed, others
minimal chan#e
minimal chan#e
>nterstitium W;5 early
>nterstitium W;5 early
Scarrin#
Scarrin#
K=CA5 SEA@E;0A5
K=CA5 SEA@E;0A5
A5=@E)65=SC5E)=S>S NKSASO
A5=@E)65=SC5E)=S>S NKSASO
@ost common non9urolo#ic cause ES)%
@ost common non9urolo#ic cause ES)%
a#es !93:"
a#es !93:"
@ore common in *lacks and Hispanics
@ore common in *lacks and Hispanics
than Caucasians
than Caucasians
@ay recur post9transplantation
@ay recur post9transplantation
@ost pediatric cases are idiopathic
@ost pediatric cases are idiopathic
KSAS
KSAS
Crosso(er between @C;S and KSAS
Crosso(er between @C;S and KSAS
Steroid responsi(e patients with KSAS
Steroid responsi(e patients with KSAS
ha(e much lower incidence of renal
ha(e much lower incidence of renal
insufficiency than steroid resistant patients
insufficiency than steroid resistant patients
Common patholo#ic end9point for many
Common patholo#ic end9point for many
processesFsecondary KSKS
processesFsecondary KSKS
B
=besity, H>D, D96 reflu&, decreased nephron
=besity, H>D, D96 reflu&, decreased nephron
mass
mass
+)>@A)? KSAS
+)>@A)? KSAS
0HE)A+?
0HE)A+?
Steroid responsi(e99Qcontinuum with @C;S
Steroid responsi(e99Qcontinuum with @C;S
5on# term R"o"d" steroidsFadults
5on# term R"o"d" steroidsFadults
@endoIa +rotocol
@endoIa +rotocol
B
S
S
+ulseE steroids 8 cyclophosphamide
+ulseE steroids 8 cyclophosphamide
Cyclosporine
Cyclosporine
0acrolimusQ
0acrolimusQ
@@KQ
@@KQ
ACE and.or A)* to diminish proteinuria
ACE and.or A)* to diminish proteinuria
Kor recurrence post9transplantation
Kor recurrence post9transplantation
B
+lasmapheresis 8 CyA or cyclophosphamide
+lasmapheresis 8 CyA or cyclophosphamide
NEPHROTIC SYNDROME
PRESENTATION
STEROIDS
RESPONSE
Good prognosis
Relapses likely
NO RESPONSE
BIOPSY
FSGS
MCNS
OTHER
IMMUNOSUPPRESSION
Lae
Non!resp
Q
"ASE #!!$essi%a
&
' y(o( girl )i* +, proein-ria a ro-ine PE( No
ede.a( Neg PMH/ nor.al G 0 D
&
BUN12+ .g3dl/ S %r14(5 .g3dl
&
S al617(5 g3dl/ %*ol1742 .g3dl
&
#+ *o-r -rine proein1+(8 gra.s
&
Nor.al "7/ neg ANA
&
Prednisone + )eeks a # .g3kg3day/ no response
&
Renal 6iopsy19SGS
&
"y%lop*osp*a.ide non!responsi:e
&
No ;-r*er rea.en e<%ep A"E in*i6ior
"ase 7!!T*e siser/ $-lie
&
7!+, proein-ria ;o-nd a age 5 =6y *er .o*er> )i*
dip si%ks gi:en es *er siser/ $essi%a?s/ -rine
&
Nor.al PE/ BP @#35A
&
U3A17, proein/ o%%asional r6%
&
#+ *r U proein1 2(' g
&
S %rea14(5 .g3dl/ S al617(@ g3dl
&
Biopsy19SGS
&
T*erapy!!A"E in*i6ior only
&
Menar%*e age 22
Jessica (cont)
&
Pri.ary a.enorr*ea age 28
&
Urine pro3%r18('/ s %r12(4 .g3dl
&
Tanner # 6reass/ -na.6ig-o-s ;e.ale Tanner III
genialia
&
Bery *ig* gonadoropins
&
Caryoype +8 DY
&
SRY presen 6y 9ISH
&
S-rgi%al e:al-aion s*o)ed sreak gonads )i*
se:eral adeno.as/ s.all -er-s
&
No e:iden%e o; kidney -.or
&
Beg-n on repla%e.en esrogen3progesin
9RASIER SYNDOME
&
Proein-ria in a p*enoypi%ally nor.al
;e.ale/ 9SGS/ renal ins-;;i%ien%y 6y
adoles%en%e or yo-ng ad-l*ood
&
Nor.al ;e.ale e<ernal genialia/ pri.ary
a.ennor*ea
&
Sreak gonads/ DY karyoype =)i* nor.al
se< deer.ining gene/ SRY>
&
gonado6laso.a/ 6- no repored Eil.?s
-.or
Eil.s T-.or S-ppressor Gene!!
ET2
&
"*ro.oso.e 22p27
&
E<pression peaks d-ring e.6ryogenesis/
espe%ially in .eso! and .eanep*ros(
&
Persisen e<pression in .a-re podo%yes
s-ggess ET2 ne%essary ;or er.inal
di;;ereniaion and proper ;-n%ion
&
ET2 kno%k o- .i%e la%k kidneys or gonads
&
Bo* girls *a:e a .-aion a e<on @ o; ET2
Normal Glomerular Caillar!
Glomerular "arriers to Proteinuria
Glo.er-lar 6ase.en
.e.6rane =GBM>
Epi*elial
%ell ;oo
pro%esses
Endo*elial
%ell )i*
;enesraions
Proein
T*e glo.er-lar Podo%ye
Direction
of
filtration
Copyri#ht T3::! American +hysiolo#ical Society
(ryggvason" .+ et al+ Physiology #$$53#$40%8/$/
A)GU'& /+ 'enal glomerular filtration system &ach human kidney contains K/"$$$"$$$
glomeruli
Mini.al "*ange Glo.er-lopa*y
Ele%ron Mi%ros%opy
Nor.al
9oo pro%ess e;;a%e.en
Modified from4 Curr Opin Genet Dev #$$/3 //4>##
Podocyte foot process
&ndothelial cell
Direction of
filtration
CD#,P
8actinin8!
GCM
Urinary space
Slit diaphragm
made of nephrin
molecules from
t6o opposite foot
processes
A8actin
Podocin
Nephrin
AE;E0>C E0>=5=A>ES
AE;E0>C E0>=5=A>ES
;ephrotic syndrome
;ephrotic syndrome
CH>5%H==% =;SE0 CH>5%H==% =;SE0
B
W01 W01 Krasier syndromeFA% Krasier syndromeFA%
%enys9%rash Syndrome %enys9%rash Syndrome
B
+AU93 +AU93 N)enal Coloboma syndrome99A)O N)enal Coloboma syndrome99A)O
B
;+HS1 ;+HS1 Nnephrin99con#enital nephrotic syndrome Nnephrin99con#enital nephrotic syndrome
Kinnish type99A)O Kinnish type99A)O
B
;+HS3 ;+HS3 Npodocin99A)O Npodocin99A)O
A%650 =;SE0 A%650 =;SE0
B
1-R11 1-R11 Nalpha9actinin99A%O Nalpha9actinin99A%O
B
0)+C94 0)+C9499A% 99A%
+odocinF;+HS93
+odocinF;+HS93
>n Europe, accounts for V !:L familial ;S
>n Europe, accounts for V !:L familial ;S
and /93:L sporadic S);S
and /93:L sporadic S);S
@ost patients ha(e KSAS
@ost patients ha(e KSAS
@ost present first decade
@ost present first decade
@ore than !: mutations identified
@ore than !: mutations identified
@ost do not respond to immunosuppressi(es
@ost do not respond to immunosuppressi(es
HeteroIy#ote carriers #enerally unaffected
HeteroIy#ote carriers #enerally unaffected
NEPHROTIC SYNDROME
PRESENTATION
STEROIDS
RESPONSE
Good prognosis
Relapses likely
NO RESPONSE
BIOPSY
FSGS
MCNS
OTHER
FGENETI" S"REENINGF
IMMUNOSUPPRESSION
neg
Lae
Non!resp
SYMPTOMATI" R< ONLY
NPHS# E!2
