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 ?

Massive proteinuriaPrimary symptom

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. 4 th edition. Baltimore: Lippincot Wiliams & Wilkins;1999. p. 732.

Pathogenesis of nephrotic syndrome

DAMAGED ProteinuriaMaintain barrierfunction

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

PATHOGENESIS OF NEPHROTIC SYNDROME

Loosingpodocyte 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. 3 rd edition. Baltimore: Oxford University Press;2003. p. 344-7.

Pathogenesis of nephrotic syndrome

Filtration route

Restriction Molecules > 10 kDa

Electrostatic( negative charge)

Disfunction

Non selectiveproteinuria

Selectiveproteinuria

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

NS

All the drugs known to be effective have effects to

the immune system Certain infections that depress T-cell function arecapable of inducing remissions

MCNS is associated with Hodgkin’sDisease and other lymphomas

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 paediatric nephrology. 3rd edition. Baltimore.2003. Oxford University Press. p. 343.

Signals that influence TH differentiationGimbert P, et al. Recent approach to the pathogenesis of minimal-change nephritic syndrome. Nephrol dial transplant 2003;18:245-8

TNF-α, IL-8,VPF, VEGF, GPF, SIRS

Immunological sequence of events leading to abnormal T-cell response

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

Geneticmutations 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 onsetCNF NPHS1 Nephrin AR Prenatal, __

19q13.1 early childhoodSNRS NPHS2 Podosin AR Childhood __

1q25-31 early adulthoodFSGS1 ACTN4 α4actinin AD early adulthood __

19q13FSGS2 TRPC6 TRPC6 AD Adulthood __

11q21-22FSGS3 CD2AP CD2AP AD ? __(mencit) 6p12Sindrom Frasier WT1 Transcription AD early Pseudohermafro- Sindrom Denys- 11p13 factor childhood ditisme+Tumor Drash WilmsSindrom Pierson LAMB2 lamininβ2 AR Prenatal Eye abnormalities 3p14-22 chain -microcoria Diffuse mesangial NPHS3 ARslerosisReference: 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)I. NEPHRIN (NPHS1)

• Encoding nephrin• Localized on chromosome 19q13.1• The first gene correlated with nephrotic syndrome

• Encoding nephrin• Localized on chromosome 19q13.1• The first gene correlated with nephrotic syndrome

• Protein, 136 kDa• The first molecule had been found on slit diaphragm • Normal architecture and glomerular basale membrane function and play role in management of signaling pathway

• Protein, 136 kDa• The first molecule had been found on slit diaphragm • Normal architecture and glomerular basale membrane function and play role in management of signaling pathway

NPHS1 NEPHRIN

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

I. NEPHRIN (NPHS1)I. NEPHRIN (NPHS1)

•Nephrin is synthesized by podocyte (glomerular epithelium)•Localized at slit diaphragm•Mutations Renal lesion in one month

Glomerulo sclerosis

ProgressiveMesangialsclerosis

Capillaryobliteration

Ultrastructuralchanges& podocyte hypertrophy

Endocapillary lesions

Pollak M. Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol 2000; 13: 3016-23

Congenital nephrotic syndrome of the Finnish type(CNF)

CNF

Severe NS

Early onset proteinuria: Neonatal period

Progressive Renal failure

Prematurity(35-38 weeks)Placenta weight :25% the birth weight

Edema present at birthor during the first week

of life

Hypoalbuminemia &hypogammaglobulinemi

aDisorder of nutritional

Risk of infectionThromboemboly

Steroid resistant &

immunosupresive

CLINICAL ASPECTS OF NPHS1 MUTATIONS

Niaudet P. Genetic forms of nephrotic syndrome. Pediatr Nephrol 2004; 19(12): 1313-18

NEPHRIN

1998 1999

CD2AP

Role of genetics in nephrotic syndrome pathogenesis

Neng-Yao Shih. Congenital Nephrotic Syndrome in Mice Lacking CD-2 Associated Protein. Science, 1999

II. CD2-Associated Protein (CD2AP)II. CD2-Associated Protein (CD2AP)

Click to add Title1 Expressed primarily in podocytes at the cytoplasmic of the SD

Click to add Title2 Mutations FSGS with extracellular matrix deposition

Click to add Title1 Extensive foot processes effacement

Click to add Title1 The role of CD2AP in NS was found in mice, which 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

Chromosome 6p12Click to add Title1 Chromosome 6p12

Role of genetics in nephrotic syndrome pathogenesis

NEPHRIN

1998 1999

CD2AP PODOCIN

2000

Nicholas Boute. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid resistant nephrotic syndrome. Nat. Genetics , 2000

III. Podocin (NPHS2)

(3) As a linker between the plasma membrane (nephrin) and the cytoskeleton podocyte

(2) Podocin stomatin protein family, expressed on podocyte foot processes

(1) Chromosome 1q25-q31, BM: 42 kD

(4) Stabilizing interactions structural integrity & functional SD

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

III. Podocin (NPHS2)III. Podocin (NPHS2)

Protein membrane integrated about 30 kD, with terminal N and C in intracellular

Ruangintraseluler

Ruangekstraseluler

6-21 % NSRS NPHS2 mutationsFSGS The risk of relapse after

transplantation is low NPHS2 recessive mutations Only

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

1998 1999

CD2AP PODOCIN

2000

WT1

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)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

NEPHRIN

1998 1999

CD2AP PODOCIN

2000

TRCP 6

Role of genetics in nephrotic syndrome pathogenesis

2005

Michelle P. Winn. A mutation in the TRCP6 Cation Channel Causes Familial Focal Segmental Glomerulosclerosis. Science, 2005

WT1

2002

IV. Transient Receptor Potential 6 (TRCP6)IV. Transient Receptor Potential 6 (TRCP6)

Structure regulation and normal podocytes function

Chromosome 11q24

A member of superfamily

Transient Receptor Potential

MutationFSGS Autosomaldominant

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

NEPHRIN

1998 1999

CD2AP PODOCIN

2000

TRCP 6ΑCTN-4

Role of genetics in nephrotic syndrome pathogenesis

2005 2005

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

WT1

2002

V. Alpha-actinin 4 (ACTN-4)

1

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

Missense mutationsUncommon than NPHS1 & NPHS2 mutations

FSGS caused by this gene mutations is autosomaldominant Late onset, the progressivity is low

Lies on chromosome 19q13, linked to FSGS Homodimer 100 kDMaintains the shape of podocyte foot processes

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

Role of genetics in nephrotic syndrome pathogenesis

NEPHRIN

1998 1999

CD2APPODOCIN

2000

TRCP 6ACTN-4

WT1 LAMB2

20052005

2002 2006

Obeidova. Genetic basis of nephrotic syndrome-review. Prague Med report, 2006

VII. Laminin β2 chain (LAMB2)VII. Laminin β2 chain (LAMB2)

• Encoding laminin β2 chain, expressed on glomerular basale membrane artery, lenses capsule, retina, neuromuscular synaps

Gene mutations cause Pierson syndrome

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

NEPHRIN

1998 1999

CD2APPODOCIN

2000

TRCP 6ACTN-4

WT1LAMB2 NPHS3

200820052002 20062005

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.

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