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

Response to steroid

Histopathology:

Sensitive

Minimal

Resistant

Non minimal Mainly FSGS

Pathogenesis of nephrotic syndrome

DAMAGED

Proteinuria

Maintain barrier function

Pathogenesis of nephrotic syndrome
Filtration route

Restriction Molecules > 10 kDa

Electrostatic ( negative charge)

Disfunction
Non selective proteinuria Selective 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, µ97.

Immunological basis

Genetic basis

Studies have shown nephrotic syndrome results from

Abnormal regulation of T-cell subsets

Expression of a circulating glomerular 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.

Reactive Oxygen Species (ROS) and Cytokines Other than Cytokines VPF 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  Galectin.  Osteopntin

Heparanase is an enzyme A plasma to modulate directly able factor (100 the KF) from patients with selective permeability of the steroid sensitive glomerular capillary wall by nephrotic syndrome, degrading HSGAG, which which is able to reduce constitutes the charge glomerular barrier. sialoglycoproteins in
vivo and cause 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 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 the immune system

Certain infections that depress T-cell function are capable of inducing remissions

Increased incidence of atopy in affected children and family

NS
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 known anti-inflammatory glucocorticoids. The including IV pulse 

and immunosuppressive activities of glucocorticoids have been taken as indirect evidence suggesting that frequent use, action in NS Despite their their mechanism of however, neither involves inhibition of release of soluble mediators the target cell nor the mechanism of action of by 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 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 

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 upregulated 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 NEPHRIN PODOCIN

WT1

TRCP 6 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.

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