PATHOGENESIS

OF
NEPHROTIC SYNDROME
 Massive Proteinuria
(≥ 50 mg/kg body weight /day/ ≥ 40
mg/m2/hour / urine protein/creatinin
ratio > 2 mg/mg / dipstick ≥ +2)

Hypoalbuminemia < 2,5 g/dL

Edema

Hyperlipidemia

Roth KS. Nephrotic syndrome: Pathogenesis and management. Ped in Rev 2002;23(7):237-47
 T cell disfunction &
Genetic mutations

Immunology & genetics

Mechanism ?

Primary
symptom Massive proteinuria

Obeidova H. Genetic basis of nephrotic syndrome-review. Prague Med report 2006; 107(1) 5-
16.
 Classification of Nephrotic
syndrome

Barratt TM. Steroid responsive nephrotic syndrome. In: Barratt TM, editor. Pediatric nephrology. 4th edition.
Baltimore: Lippincot Wiliams & Wilkins;1999. p. 732.
Pathogenesis of nephrotic syndrome

Maintain
DAMAGED
Proteinuria barrier
function

McBryde KD. Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr.2001;31:275-307

 PATHOGENESIS OF NEPHROTIC SYNDROME

Loosing
podocyte foot
processes

•Change of permeability
•Structural changes of
foot processes

Haycock G. The child with idiopathic nephrotic syndrome. In: Postlethwaite R, editor. Clinical paediatric nephrology. 3rd edition. Baltimore:
 Pathogenesis of nephrotic syndrome

Filtration route

Restriction Electrostatic
Molecules > 10 kDa ( negative charge)

Disfunction
Non selective Selective
proteinuria proteinuria

Haycock G. The child with idiopathic nephrotic syndrome. In: Postlethwaite R, editor. Clinical
paediatric nephrology. 3rd edition. Baltimore: Oxford University Press;2003. p. 344-7.
 Circumstantial evidence that nephrotic
syndrome had an immunological basis

All the drugs known to be

effective have effects to Certain infections that
the immune system depress T-cell function are
capable of inducing
remissions

Increased incidence
of atopy in affected
NS
children and family
MCNS is associated with
Hodgkin’s
Disease and other
lymphomas
Children with NS are
susceptible to bacterial
peritonitis and sepsis
especially S.pneumoniae

Haycock G. The child with idiopathic nephrotic syndrome. In: Postlethwaite R, editor. Clinical paediatric
nephrology. 3rd edition. Baltimore.2003. Oxford University Press. p. 343.
 Signals that influence TH differentiation
Gimbert P, et al. Recent approach to the pathogenesis of minimal-change nephritic syndrome. Nephrol dial transplant 2003;18:245-8
 Immunological sequence of events leading
to abnormal T-cell response

TNF-α, IL-8,
VPF, VEGF,
GPF, SIRS

Gimbert P, et al. Recent approach to the pathogenesis of minimal-change nephritic syndrome. Nephrol dial transplant 2003;18:245-8
 Role of genetics in nephrotic
syndrome pathogenesis

• Incidence: 3-5%
•Relation with:
- Autosomal recessive or dominant
- FSGS
- Steroid resistant
Genetic
mutations Diagnosis
&
Treatment
8 genes had been
found
Hinkes BG. NPHS3: new clues for understanding idiopathic nephrotic syndrome. Springer Berlin/Heidenberg 2008
 Role of genetics in nephrotic syndrome
pathogenesis
Genes responsible for inherited nephrotic syndrome

Disease Gene+ Protein Inheritance Age of

Anomalies
Localisation onset
CNF NPHS1 Nephrin AR Prenatal, __
19q13.1 early childhood
SNRS NPHS2 Podosin AR Childhood __
1q25-31 early adulthood
FSGS1 ACTN4 α4actinin AD early adulthood __
19q13
FSGS2 TRPC6 TRPC6 AD Adulthood __
11q21-22
FSGS3 CD2AP CD2AP AD ? __
(mencit) 6p12
Sindrom Frasier WT1 Transcription AD early Pseudohermafro-

Sindrom Denys- 11p13 factor childhood ditisme+Tumor

Drash Wilms
Sindrom Pierson LAMB2 lamininβ2 AR Prenatal Eye
abnormalities
3p14-22 chain -microcoria

Diffuse mesangial NPHS3 AR

slerosis
Reference: Obeidova H, Merta M, Reiterova J, dkk. Genetic basis of nephrotic syndrome-review. AR:autosomal
recessive
Prague Med report. 2006;107(1): 5-16 AD:autosomal dominant
Role of genetics in nephrotic
syndrome pathogenesis
NEPHRIN

1998

NEPHRIN

Positionally Cloned Gene for a Novel Glomerular Protein-

Nephrin- is mutated in congenital nephrotic syndrome
 I. NEPHRIN (NPHS1)

NPHS1 NEPHRIN
• Protein, 136 kDa
• The first molecule
• Encoding nephrin had
• Localized on been found on slit
chromosome diaphragm
19q13.1
• The first gene • Normal architecture
correlated and glomerular
with nephrotic basale membrane
syndrome function
and play role in
management of
signaling pathway

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005; 72: 777-84
 I. NEPHRIN (NPHS1)

•Nephrin is synthesized by podocyte (glomerular epithelium)

•Localized at slit diaphragm
•Mutations  Renal lesion in one month

Ultrastructural
changes
Progressive Capillary & podocyte
Glomerulo Mesangial obliteration hypertrophy
sclerosis sclerosis

Endocapillary lesions
Pollak M. Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol
2000; 13: 3016-23
 CLINICAL ASPECTS OF NPHS1 MUTATIONS

Congenital nephrotic syndrome of the Finnish

type(CNF) Severe
Progressive
NS  Renal
failure

Steroid resistant
& Early onset
immunosupresive proteinuria:
Neonatal period
Hypoalbuminemia & CNF
hypogammaglobulinemi Prematurity
a (35-38 weeks)
Disorder of nutritional Placenta weight :
Risk of infection 25% the birth
Thromboemboly weight
Edema present at birth
or during the first week
of life
Niaudet P. Genetic forms of nephrotic syndrome. Pediatr Nephrol 2004; 19(12): 1313-18
Role of genetics in nephrotic
syndrome pathogenesis
NEPHRIN CD2AP

1998 1999

Neng-Yao Shih. Congenital Nephrotic Syndrome in Mice Lacking CD-2

Associated Protein. Science, 1999
 II. CD2-Associated Protein (CD2AP)

1 ChromosomeChromosome
6p12 6p12
Click to add Title

1 Expressed primarily
Clickintopodocytes
cytoplasmic of the SD
add Titleat the

2 Clickwith
Mutations FSGS to add Title matrix deposition
extracellular

1 Extensive footClick
processes effacement
to add Title

1 The role of CD2APClick

in NS was
to found
add in mice, which
Title
developed a NS and die at 6 weeks of age with renal failure.
In human still unclear.

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:777-84

 Role of genetics in nephrotic
syndrome pathogenesis

NEPHRIN CD2AP PODOCIN

1998 1999 2000

Nicholas Boute. NPHS2, encoding the glomerular protein podocin, is mutated in

autosomal recessive steroid resistant nephrotic syndrome. Nat. Genetics , 2000
III. Podocin (NPHS2)
(1) Chromosome
1q25-q31, BM: 42 kD

(3) As a linker
between the plasma
membrane (nephrin)
(2) Podocin  and the cytoskeleton
stomatin protein
podocyte
family, expressed
on podocyte foot
processes

(4) Stabilizing interactions

structural integrity &
functional SD

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:777-

84
 III. Podocin (NPHS2)

Ruang Ruang
intraseluler ekstraseluler
6-21 % NSRS  NPHS2 mutations
FSGS The risk of relapse after
Protein membrane integrated transplantation is low
about 30 kD, with terminal NPHS2 recessive mutations  Only
N and C in intracellular 1 child in 1 family

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:777-84

 Role of genetics in nephrotic
syndrome pathogenesis

NEPHRIN
CD2AP
PODOCIN WT1

1998 1999 2000 2002

Jian-Kan Guo. WT1 is a Regulator of podocyt function : reduced expression

level cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol
Gen, 2002
 VI. Wilms’ Tumor Gene (WT1)

• Chromosome 11p13, is composed of 10 exons

• Encodes Four zinc finger
• Ekspression of normal WT1 Important for normal renal
and genital development, renal
induction and nephrogenesis
• Typical mutations  Sporadic Wilms’ tumor
• Association with Frasier syndrome & Denys-Drash
syndrome  Gonadal dysfunction and progressive
nephropathy (FSGS)
• Onset: Early childhood
• Association to podocyte function still unclear

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:777-84

Role of genetics in nephrotic
syndrome pathogenesis
NEPHRIN CD2AP PODOCIN WT1 TRCP 6

1998 1999 2000 2002 2005

Michelle P. Winn. A mutation in the TRCP6 Cation Channel Causes

Familial Focal Segmental Glomerulosclerosis. Science, 2005
 IV. Transient Receptor Potential 6 (TRCP6)

Chromosome
11q24
Structure
MutationFSGS regulation
Autosomal and normal
dominant podocytes
A member of
function
superfamily
Transient Receptor
Potential

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:777-84

 Role of genetics in nephrotic syndrome
pathogenesis
TRCP 6
NEPHRIN CD2AP PODOCIN WT1 ΑCTN-4

1998 1999 2000 2002 2005 2005

Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Paedtr 2005

 V. Alpha-actinin 4 (ACTN-4)

Lies on chromosome
Component 19q13,
of the actin linked to
cytoskeleton FSGS
that binds to F actin and the gene.
Homodimer 100 kD 19q13, linked to FSGS
Lies on chromosome
Maintains the shape
Homodimer 100 kDof podocyte foot processes
Maintains the shape of podocyte foot processes

Missense mutations
Uncommon than NPHS1 & NPHS2 mutations

1 caused by this gene mutations is

FSGS
autosomal
dominant
 Late onset, the progressivity is low
Obeidova H. Genetic basis of nephrotic syndrome-review. Prague Med report 2006; 107(1)5-16
 Role of genetics in nephrotic
syndrome pathogenesis

NEPHRIN CD2AP PODOCIN WT1 TRCP 6 LAMB2

ACTN-4

1998 1999 2000 2005 2006

2002 2005

Obeidova. Genetic basis of nephrotic syndrome-review. Prague Med

report, 2006
 VII. Laminin β2 chain (LAMB2)

• Encoding laminin β2
chain, expressed on Gene
glomerular mutations
basale membrane artery, cause Pierson
lenses capsule, retina, syndrome
neuromuscular synaps
Autosomal recessive, with congenital
nephrotic syndrome manifestations
and spesific eye abnormalities.
Histopathology: diffuse mesangial
sclerosis
Obeidova H. Genetic basis of nephrotic syndrome –review. Prague Med report 2006;107(1):5-16.
 Role of genetics in nephrotic
syndrome pathogenesis

CD2AP WT1 TRCP 6

NEPHRIN PODOCIN ACTN-4 LAMB2 NPHS3

1998 1999 2000 2002 2005 2005 2006 2008

Hinkes BG. NPHS3: new clues for understanding idiopathic nephrotic syndrome.
Springer Berlin/Heidenberg 2008.
Hinkes BG. NPHS3: new clues for understanding idiopathic nephrotic syndrome. Springer
Berlin/Heidenberg 2008.
THANK YOU !