Hanan Fathy

Pediatric Nephrology Unit

 Massive Proteinuria
(≥40mg/m2/hour/≥1mg/m2/day/
urine protein/creatinine
ratio>2mg/mg / dipstick ≥ +3)

Hypoalbuminemia < 2,5 g/dL

Edema

Hyperlipidemia
Pathogenesis of nephrotic syndrome

Maintain
DAMAGED barrier
Proteinuria
function
Pathogenesis of nephrotic syndrome

Filtration route

Restriction Electrostatic
Molecules > 10 kDa ( negative charge)

Disfunction
Non selective Selective
proteinuria proteinuria
Podocyte foot process effacement is
a hallmark of nephrotic syndrome
Reorganization of the podocyte actin
cytoskeleton during foot process effacement
Proteoglycan Coat of Fenestrated
Endothelia: Glomerular Endothelium

From: Rostgaard J & Qvortrup K Electron Microscopic Demonstrations of Filamentous

Molecular Sieve Plugs in Capillary Fenestrae. Microvasc. Res. 53: 1-13, ‘97.
Immunological
Immunological basis
basis
Genetic
Geneticbasis
basis
 Studies have shown
nephrotic syndrome results from

Expression of
Abnormal regulation of a circulating glomerular
T-cell subsets vascular permeability factor.
Abnormal regulation of
T-cell subsets
Pathogenetic Cells in Idiopathic
Nephrotic Syndrome
B- Cells
 Recent clinical observations that remission can be
achieved by depletion of B-cells using monoclonal
antibodies, contradict the scenario of T-cell disorder
based pathogenesis of INS
Other Cells

 Scientiests . were also interested in CD34+ stem cells as

an important player in the pathogenesis of INS.

 They have shown that CD34+ cells obtained from

patients with INS and injected into mice may be
engrafted and could induce albuminuria in mice.

 Thus, CD34+ hematopoietic stem cells are being

highlighted as the important cells in the pathogenesis of
INS
 Expression of
a circulating glomerular
vascular permeability factor.

Cytokines Reactive Oxygen Species (ROS) and

VPF Other than Cytokines
Reactive Nitrogen Species (RNS)
Candidates of Vascular Permeability
Factor (VPF)

 Cytokines:
Increased levels of cytokines in serum or urine
in relapse were reported in:

Interleukin (IL)-2 , soluble IL-2 receptor ,

interferon-gamma,
IL-4 , IL-12 , IL-18 , tumor necrosis factor (TNF)-
and vascular endothelial growth factor (VEGF) .
VPF Other than Cytokines

 Hemopexin (heme-binding acute phase

reactant)
 Heparanase
Heparanase
Heparanaseisisan anenzyme
enzyme
 Galectin. A plasma
directly
directly able
ableto
A plasma factor (100
tomodulate
factor (100 the
modulate the
KF)
selectivefrom
KF) from patients
permeability with
of
patients with the
 Osteopntin selective
steroid
steroid
glomerular
permeability
sensitive
sensitive
capillary
of
wall
the
glomerular
nephrotic capillary
syndrome, wallby
by
nephrotic
degrading syndrome,
HSGAG, which
degrading
which
which is
is
HSGAG,
able
ableto
to
which
reduce
reduce
constitutes
constitutes the charge
glomerular charge
glomerular the
barrier.
barrier.
sialoglycoproteins
sialoglycoproteinsinin
vivo
vivoand
andcause
cause
proteinuria
proteinuria
 Reactive Oxygen Species (ROS) and
Reactive Nitrogen Species (RNS)

 NO is a typical free-radical gas synthesized

from L-arginine by three isoforms of NOS and
physiologically serves many functions within
the kidney, such as
 Regulation of vascular tone,
 Renal hemodynamics,
 Modulation of fluid and electrolyte transpor
Inducible nitric oxide synthase (NOS) are expressed
in neutrophils, and mononuclear phagocyte.
In addition, it was recently shown that peripheral
blood T-cells are also NO-producing cells .

It is believed that
pro du c ed by ly m p h ocytes
NO
p la y a n im p ort an t role in
may
p a th o ge ne s is o f IN S.
the
 It was observed that ROS are possible mediators of
glomerular injury , patients with INS disclose an
imbalance between oxidant and antioxidant
activity.

 This idea was further supported by the fact that

an injection of antioxidants in experimental models
of nephrotic syndrome has been found to be
ameliorative .

 Hence the suggestion of the therapeutic possibility

that the glomerular injury in MCNS can be
attenuated by free radical scavengers in vivo.
 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.
Focusing on the podocyte
 Focusing on the podocyte
 A key type of cell in the glomerular capillary
wall that is believed to prevent proteinuria in
healthy persons.

 The podocyte’s function depends on a

complex and unique structure that, in turn,
depends on a tightly regulated actin
cytoskeleton
Podocyte Proteome
 Podocyte foot process effacement
is a hallmark of nephrotic
syndrome

 Effacement is dependent on disruption of the

actin cytoskeleton network in the podocytes,
 The most commonly used treatment for NS is
oral glucocorticoids, with secondary
treatments including
The known IV pulse glucocorticoids.
anti-inflammatory
and immunosuppressive activities of glucocorticoids
have been taken as indirect evidence
 suggesting
Despite that their
their mechanism
frequent use, of however,
action in NS neither
involves inhibition of release of soluble mediators
the target cell by nor the mechanism of action of
T-lymphocytes.
glucocorticoids in inducing remission in
patients with NS was identified.
 Recently, however, podocytes have
been shown to contain the
glucocorticoid receptor.

The receptor has been shown to

translocate to the nucleus upon
steroid treatment, suggesting that
glucocorticoids may in fact act directly
on podocytes.
 Glucocorticoids (GC)
 Can act via genomic or non-genomic mechanisms
 Genomic effects
 Mediated by GC receptor (GR)
 GR-hormone complex moves to nucleus to affect transcription.
 Resulting effects mediated by alterations in protein expression.
(Kidney Int 56, 65-73)

 GC treatment of cultured podocytes can: (Kidney Int 68, 2473-83)

 Protect and enhance recovery from injury.
 Reduce actin filament disruption.
Dexamethasone Protects Podocytes Against Injury.
 Authors also found that:
 Cyclosporine, the effectiveness of which has
often been described as evidence of a key
etiologic role for T lymphocytes in proteinuric
diseases, has direct effects on the actin
cytoskeleton (and therefore the shape) of
podocytes.
The
Thefindings
findingsprovide
providesupport
supportthat
that
the
theantiproteinuric
antiproteinuriceffect
effectof
of
cyclosporine
cyclosporinecan canbe
beexplained
explainedbyby
its
itsdirect
directeffects
effectson
onpodocytes,
podocytes, not
not
by
byits
itsactions
actions on
onTT lymphocytes
lymphocytes
 Scientists identified a protein called c-mip that
affects the actin cytoskeleton in lymphocytes and is
upregulated in lymphocytes in patients with the
nephrotic syndrome.

 They recently observed that the same protein is up-

regulated in podocytes in proteinuric diseases.

 They also found that specific overexpression in

podocytes leads to proteinuria .

 The podocytes over expressing c-mip had the same

morphologic characteristics as those of human
proteinuric diseases, with effacement of foot
processes and loss of the cortical actin cytoskeleton.
Lymphocyte Podocyte
 The glomerular filtration barrier

Nilius, B. et al. Physiol. Rev. 87: 165-217 2007;

doi:10.1152/physrev.00021.2006

Copyright ©2007 American Physiological Society

 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

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.