Pathogenesis Of Nephrotic Syndrome

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) 516.

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

DAMAGED

Proteinuria

Maintain 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 Molecules > 10 kDa

Electrostatic ( negative charge)

Disfunction Non selective proteinuria

Selective 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 the immune system

Increased incidence of atopy in affected children and family

Children with NS are susceptible to bacterial peritonitis and sepsis especially S.pneumoniae

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

NS MCNS is associated with Hodgkin’s Disease and other lymphomas

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 Genes responsible for inherited nephrotic syndrome pathogenesis Disease

Gene+ Anomalies Localisation CNF NPHS1 19q13.1 SNRS NPHS2 1q25-31 FSGS1 ACTN4 19q13 FSGS2 TRPC6 11q21-22 FSGS3 CD2AP (mencit) 6p12 Sindrom Frasier WT1 Sindrom DenysDrash Sindrom Pierson abnormalities

Protein Nephrin

AR

Podosin

AR

α4actinin

AD

TRPC6

AD

Adulthood

__

CD2AP

AD

?

__

Transcription

factor

LAMB2

lamininβ2

Diffuse mesangial NPHS3 slerosis

Age of

onset Prenatal, early childhood Childhood early adulthood early adulthood

11p13

3p14-22

Inheritance

AD

early childhood

AR

chain

Prenatal

__ __ __

Pseudohermafroditisme+Tumor Wilms Eye -microcoria

AR

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 ProteinNephrin- is mutated in congenital nephrotic syndrome

I. NEPHRIN (NPHS1) NPHS1 • Encoding nephrin • Localized on chromosome 19q13.1 • The first gene correlated with nephrotic syndrome

NEPHRIN

• 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

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

Glomerulo sclerosis

Progressive Mesangial sclerosis

Capillary obliteration

Ultrastructural changes & podocyte hypertrophy

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 & immunosupresive

Hypoalbuminemia & hypogammaglobulinemi a Disorder of nutritional Risk of infection Thromboemboly

CNF

Early onset proteinuria: Neonatal period

Prematurity (35-38 weeks) Placenta weight : 25% the birth 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 add Titleat the cytoplasmic of the SD

2

Mutations FSGS extracellular Clickwith to add Title matrix deposition

1

Extensive footClick processes effacement to add Title

1

The role of CD2APClick in NS was found in mice, which to add 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

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

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

(4) Stabilizing interactions structural integrity & functional SD Vats AN. Genetics of idiopathic nephrotic syndrome. Indian J Pediatr 2005;72:77784

III. Podocin (NPHS2)

Ruang intraseluler

Ruang ekstraseluler

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

6-21 % NSRS  NPHS2 mutations FSGS 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

CD2AP

1999

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) • 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

1998

1999

2000

WT1 TRCP 6

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 MutationFSGS Autosomal dominant

A member of superfamily Transient Receptor Potential

Structure regulation and normal podocytes function

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

TRCP 6 ΑCTN-4

2005

2005

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

V. Alpha-actinin 4 (ACTN-4) Lies on chromosome 19q13, linked to FSGS Component of the actin cytoskeleton that binds to F actin and the gene. Homodimer 100 kD 19q13, linked to FSGS Lies on chromosome Homodimer 100 kDof podocyte foot processes Maintains the shape Maintains the shape of podocyte foot processes

Missense mutations Uncommon than NPHS1 & NPHS2 mutations

FSGS 1 caused by this gene mutations is 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

1998

1999

2000

2002

ACTN-4

2005

TRCP 6

2005

LAMB2

2006

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 NEPHRIN

1998

CD2AP

1999

WT1 PODOCIN

2000

TRCP 6 ACTN-4

2002 2005

2005

LAMB2

NPHS3

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 !