copy of updates in nephrotic

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Hanan Fathy

Pediatric Nephrology Unit


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Massive Proteinuria

(40mg/m2/hour/1mg/m2/day/urine protein/creatinine

ratio>2mg/mg / dipstick +3)

Hypoalbuminemia < 2,5 g/dL

Edema

Hyperlipidemia


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Response tosteroid

Sensitive

Resistant

Histopathology:

Minimal

Non minimal Mainly

FSGS


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Pathogenesis of nephrotic syndrome

DAMAGEDProteinuria

Maintain

barrier

function


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Pathogenesis of nephrotic syndrome

Filtration route

RestrictionMolecules > 10 kDa

Electrostatic( negative charge)

DisfunctionNon selective

proteinuria

Selective

proteinuria


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Podocyte foot process effacement is

a hallmark of nephrotic syndrome


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Reorganization of the podocyte actin cytoskeleton

during foot process effacement


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From: Rostgaard J & Qvortrup K Electron Microscopic Demonstrations ofFilamentous

Molecular Sieve Plugs in Capillary Fenestrae. Microvasc. Res. 53: 1-13, 97.

Proteoglycan Coat of Fenestrated

Endothelia: Glomerular Endothelium


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Immunological basisGenetic basis


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Abnormal regulation of

T-cell subsets

Expression of

a circulating glomerular

vascular permeability factor.

Studies have shownnephrotic syndrome results from


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Abnormal regulation of

T-cell subsets


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Pathogenetic Cells in Idiopathic

Nephrotic Syndrome


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B- Cells

Recent clinical observations that remission can beachieved by depletion of B-cells using monoclonalantibodies, contradict the scenario of T-celldisorder based pathogenesis of INS


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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 frompatients with INS and injected into mice may beengrafted and could induce albuminuria in mice.

Thus, CD34+ hematopoietic stem cells are beinghighlighted as the important cells in the pathogenesis ofINS


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Expression of

a circulating glomerularvascular permeability factor.

CytokinesVPF Other than CytokinesReactive Oxygen Species (ROS) and

Reactive Nitrogen Species (RNS)


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Cytokines:

Increased levels of cytokines in serum or urine

in relapse were reported in:

Candidates of Vascular Permeability Facto

(VPF)

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) .


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VPFOther than Cytokines

Hemopexin (heme-binding acute phase

reactant)

Heparanase Galectin.

Osteopntin

A plasma factor (100

KF) from patients with

steroid sensitive

nephrotic syndrome,

which is able to reduce

glomerular

sialoglycoproteins in

vivo and cause

proteinuria

Heparanase is an enzyme

directly able to modulate the

selective permeability of the

glomerular capillary wall by

degrading HSGAG, whichconstitutes the charge

barrier.


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Reactive Oxygen Species (ROS) andReactive

Nitrogen Species (RNS)

NO is a typical free-radical gas synthesized

from L-arginine by three isoforms of NOS andphysiologically serves many functions withinthe kidney, such as

Regulation of vascular tone,

Renal hemodynamics,

Modulation of fluid and electrolyte transpor


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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 .


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It was observed that ROS are possible mediators of

glomerular injury , patients with INS disclose animbalance between oxidant and antioxidantactivity.

This idea was further supported by the fact thatan injection of antioxidants in experimentalmodels of nephrotic syndrome has been found tobe ameliorative .

Hence the suggestion of the therapeutic possibilitythat the glomerular injury in MCNS can beattenuated by free radical scavengers in vivo.


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Circumstantial evidence that nephrotic syndrome

had an immunological basis

NS

All the drugs known to be

effective have effects to

the immune systemCertain infections that

depress T-cell function are

capable of inducing

remissions

MCNS is associated with

Hodgkins

Disease and otherlymphomas

Increased incidence

of atopy in affected

children and family

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 paediatricnephrology. 3rd edition. Baltimore.2003. Oxford University Press. p. 343.


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Focusing on the podocyte


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Focusing on the podocyte

A key type of cell in the glomerular capillary

wall that is believed to prevent proteinuria in

healthy persons.

The podocytes function depends on a

complex and unique structure that, in turn,

depends on a tightly regulated actincytoskeleton


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Podocyte Proteome


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Podocyte foot process effacement is

a hallmark of nephrotic syndrome

Effacement is dependent on disruption of theactin cytoskeleton network in the podocytes,


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The most commonly used treatment for NS is

oral glucocorticoids, with secondary

treatments including IV pulse glucocorticoids.

Despite their frequent use, however, neither

the target cell nor the mechanism of action of

glucocorticoids in inducing remission in

patients with NS was identified.

The known anti-inflammatoryand immunosuppressive activities of glucocorticoids

have been taken as indirect evidence

suggesting that their mechanism of action in NS

involves inhibition of release of soluble mediators

by T-lymphocytes.


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Recently, however, podocytes havebeen shown to contain the

glucocorticoid receptor.

The receptor has been shown to

translocate to the nucleus upon

steroid treatment, suggesting thatglucocorticoids may in fact act directly

on podocytes.


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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 Int56,65-73)

GC treatment of cultured podocytes can: (Kidney Int68, 2473-83)

Protect and enhance recovery from injury. Reduce actin filament disruption.


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Dexamethasone Protects Podocytes Against Injury.


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Authors also found that:

Cyclosporine, the effectiveness of which has

often been described as evidence of a key

etiologic role for T lymphocytes in proteinuricdiseases, has direct effects on the actin

cytoskeleton (and therefore the shape) of

podocytes.


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The findings provide support that

the antiproteinuric effect of

cyclosporine can be explained by

its direct effects on podocytes, not

by its actions on T lymphocytes


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Scientists identified a protein called c-mip thataffects the actin cytoskeleton in lymphocytes and isupregulated in lymphocytes in patients with thenephrotic syndrome.

They recently observed that the same protein is up-regulated in podocytes in proteinuric diseases.

They also found that specific overexpression inpodocytes leads to proteinuria .

The podocytes over expressing c-mip had the samemorphologic characteristics as those of humanproteinuric diseases, with effacement of footprocesses and loss of the cortical actin cytoskeleton.


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LymphocytePodocyte


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The glomerular filtration barrier


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Copyright 2007 American Physiological Society

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

doi:10.1152/physrev.00021.2006

The glomerular filtration barrier


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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


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Role of genetics in nephrotic syndrome

pathogenesis

NEPHRIN

1998 1999

CD2AP

PODOCIN

2000

TRCP 6ACTN-4

WT1LAMB2 NPHS3

200820052002 20062005

Hinkes BG. NPHS3: new clues for understanding idiopathic nephrotic syndrome.

Springer Berlin/Heidenberg 2008.


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