NEPHROTIC SYNDROME

Ozan Özkaya, MD
Professor of Pediatrics
Pediatric Nephrologist and Rheumatologist
 Objectives
⚫ Define the mechanisms of proteinuria
⚫ Define nephrotic syndrome
⚫ Understand the pathophysiology of NS
⚫ Describe the clinical and laboratory findings of NS in
children
⚫ Describe the causes of nephrotic syndrome in children
⚫ Describe the initial investigations and management of
nephrotic syndrome.
⚫ Describe the complications of nephrotic syndromes.
⚫ Decribe the pathogenesis and clinical findings of
MCNS,FSGS, membranous nephropathy
⚫ Describe the causes of congenital nephrotic syndrome
 Podocyte

Podocytes are unique cells with a complex cellular organization.

Podocytes may be divided into three structurally and functionally different
segments: cell body, major processes, and foot processes
Urinary space podocyte
foot process (pedicel)
slit diaphragm
lamina rara externa

glomerular basement membrane

lamina densa
lamina rara interna

blood
fenestrated endothelium
without diaphragms
Podocytes are unique cells with a complex cellular organization.
 Glomerular filtration barrier
Fenestrated capillary
endothelium

Glomerular basement membrane

podosit ayaklara doğru filte oluyor( ayaklara doğru işenir)

Podocyte foot processes

 Glomerular filtration barrier – glomerular
basement membrane
• High permeability to water & small
solutes

• Impermeability to proteins

- size barrier (<70,000 MW and <10 nm in diameter

proteins pass easily)

- charge barrier
• negatively charged molecules are less
able to cross the glomerulus than are
neutral molecules of identical size

Pathology:
- Proteinuria, loss of charge, slit membrane…
- Hematuria - loss of integrity, “structural” damage
 Causes of Proteinuria In Children
Intermittant Proteinuria
- Fever , exercise,emotional stress
-Postural (Orthostatic proteinuria)
Kişinin ayakta iken protein atılımının yatay

Persistant Proteinuria pozisyondaki protein atılımına oranla artmış olması

- Tubular proteinuria (β-2 mikroglobulin,lizozim)

-Glomerular proteinuria
-Overflow, proteinuria (hemoglobinuria,myoglobinuria)
 Quantification of Proteinuria
Proteinuria
1+ or higher by dipstick

24 hours collected urine

>40 mg/m2/hour
>50 mg/kg/day
>1 gr/m2/day

Spot urine
protein/creatinine>0.2
 Glomerular Proteinuria
Type of proteinuria:

Selective proteinuria: where proteins of low

molecular weight such as albumin, are
excreted more readily than protein of HMW
Non selective :
• Low molecular weight+High molecular
weight are lost in urine
 Nephrotic Syndrome

Nephrotic syndrome is a condition

characterized by proteinuria with
resultant hypoproteinemia and edema.
 Nephrotic Syndrome
Diagnosis of nephrotic syndrome
requires the presence of;

•Edema

•Massive proteinuria
>40 mg/m2/hr or a urine
protein/creatinine ratio >2.0
mg/mg)

•Hypoalbuminemia (<2.5 g/dl)

 Edema
Proteinuria
.
Hypoproteinemia

Onkotic pressure 

Shift of fluid from the vascular to

the interstitial compartment edema

Hypovolemia
tubular
Renin–angiotensin– sodium chloride
aldosterone system  reabsorption↑.
 Complications of Nephrotic Syndrome

• Increased susceptibility to infection

• Hyperlipidemia
•Thrombosis
• Protein malnutrition
•Hypovolemia
• Acute kidney İnjury
• Urinary loss of binding proteins
 Hyperlipidemia
Total cholesterol , LDL , VLDL , triglyserides , HDL 

•Decreased oncotic pressure results in increased hepatic

production of VLDL .

• Urinary loss of heparin sulfate and LCAT results in decreased

lipoprotein lipase activity with a decreased metabolism of
VLDL

• Urinary loss of HDL and LCAT results in an increased LDL/HDL

ratio
 Binding protein loss
• Vitamin D binding globulin
• IGF-1 ve 2
• Tiroid binding protein
• Transferin
• Seruloplazmin
• Cortizol binding protein
• Drug binding proteins
 Thrombosis
Increased incidence of arterial and venous thromboemboli,
particularly deep venous thrmbosis and renal vein thrombosis

• Decreased intravascular volume and immobility

• Blood viscosity
• I,II, V,VII,VIII,X and fibrinogen 
• ATIII levels 
• Protein C , Protein S 
• Platelet agregation 
• Tromboksane A-2 
• Hyperlipidemia
• Overaggressive diuresis
 o kadar protein kaybetsem ben de ımmunodeficiency olurum

Immunodeficiency

Hypogammaglobulinemia secondary to urinary

losses

Hypocomplementemia secondary to urinary

losses

Decreased cellular immunity, potentially

secondary to urinary losses of Zn and Fe
 Etiologies of Nephrotic Syndrome
(Beyond 3 Months of Age)
3 aylıktan büyük ise hastalık kaynağı idiopatik, genetik, sistemik, metabolik enfeksiyoz olabilir.

Idiopathic
•Minimal change nephrotic syndrome (MCNS)
•Focal segmental glomerulosclerosis (FSGS)
•Mesangial proliferative glomerulonephritis
•Membranoproliferative glomerulonephritis
(MPGN)
•Membranous nephropathy (MN)
•IgM nephropathy
 Etiologies of Nephrotic Syndrome (Beyond 3 Months of Age)
Genetic Infections
•Autosomal recessive FSGS due to •Hepatitis B and C
mutation in gene encoding podocin •HIV
(NPHS2) •Malaria
•Schistosomiasis
•Autosomal dominant diffuse mesangial •Filariasis
sclerosis (DMS) due to mutation in gene
encoding WT1 Systemic Diseases
•Henoch-Schönlein purpura
•Autosomal dominant FSGS due to •Systemic lupus erythematosus
mutation in gene encoding a-actinin 4 •Diabetes mellitus
•Sarcoidosis
•Autosomal dominant FSGS due to
mutation in gene encoding CD2- Metabolic Diseases
associated protein (CD2AP) •Fabry’s disease
•Glutaric acidemia
•Autosomal dominant FSGS due to •Glycogen storage disease
mutation in gene encoding transient •Mitochondrial cytopathies
receptor potential cation channel 6
(TRPC6)
 Etiologies of Nephrotic Syndrome (Beyond 3 Months of Age)
Hematologic and oncologic
Others
diseases •Bee stings (MCNS)
•Leukemia •Food allergies
•Lymphoma •Obesity (usually with FSGS)
•(Hodgkin’s most likely can lead to minimal •Oligomeganephronia
change) •Pregnancy
•Sickle cell disease
Drugs
• Nonsteroidal antiinfl ammatory drugs
•Gold
•Penicillamine
•Angiotensin converting enzyme inhibitors
•Pamidronate
•Interferon
•Mercury
•Heroin
•Lithium
 Idiopathic Nephrotic Syndrome

Steroid-Sensitive Nephrotic Syndrome:

• Patients who enter remission in response to corticosteroid treatment
alone are referred to as having steroid-sensitive nephrotic syndrome
(SSNS).

• Steroid-Resistant Nephrotic Syndrome:

Patients who fail to enter remission after 6- 8 weeks of corticosteroid
treatment are referred to as having steroid-resistant nephrotic
syndrome
 Idiopathic Nephrotic Syndrome

Steroid-Sensitive Nephrotic Syndrome (SSNS) (%75-80)

• SSNS histopathology
• MCD (80 % )
• FSGS (7-8%)
• Mesangioproliferative glomerulonephritis (MesPGN) 2.3%

Steroid-Resistant Nephrotic Syndrome: (SRNS) ( %20-25)

• SRNS histopathology
FSGS (75%)
MCD (25 (%)
Remission: Remission is characterized by a marked
reduction in proteinuria (to <4 mg/m2/hr or urine
albumin dipstick of 0 to trace for 3 consecutive
days) in association with resolution of edema and
normalization of serum albumin to at least 3.5
g/dl.

Relapse: Relapse is defined as recurrence of massive

most often in association with recurrence of edema
 Minimal Change Disease
• 90% of nephroitic syndrome in children under
the age of 10

• Most common at 1-7 years of age

• Male / Female: 2 / 1
 Pathology
• Light Microscopy
–Normal
• Immuno Fluorescence
–Negative
• Electron Microscopy:
–Loss of Foot Processes of
epithelial cells
 MCNS - Immunopathogenesis
The underlying cause of MCD is still uncertain,
however, evidence points to T-cell dysfunction as a
major player.

- Remissions of MCD occur in the setting of a measles infection

where viral associated immunosuppression occurs.
minimal change disease

- MCD occurs more frequently in patient’s with lymphoma.

- MCD is responsive to steroids and alkylating drugs.
- Atopic individuals who have exaggerated Th2 responses to
common allergens are at a higher risk of developing MCD
 MCD- Immunopathogenesis
Suspected mediators of epithelial cell injury:
A “permeability factor”of immune origin which
alters glomerular podocyte permeability causing
proteinuria:
• The nature of this circulating factor is not known.
• Various cytokines and molecules have been
implicated, including the following :
• Interleukin (IL)–2, IL-4, IL-12, IL-13, IL-15, IL-18
• Vascular permeability factor
• Nuclear factor (NF)-κB
 Pathogenesis of Proteinuria in MCD
• Increase glomerular permeability for proteins
due to loss of negative charged glycoprotein in
GBM
Loss of GBM electrical charge selectivity.
 MCD-Etiology
Idiopathic (80-90% of cases)
Secondary
▪ Drugs – NSAIDs, gold, rifampin, penicillins,
trimethadione
▪ Toxins - mercury, lead
▪ Atopic agents - bee stings, poison ivy, pollen
▪ Infection – Syphilis, Infectious mononucleosis, HIV
▪ Tumor - Hodgkin lymphoma (most commonly), other
lymphoproliferative diseases, carcinomas
▪ Other glomerular diseases – IgA nephropathy, Lupus,
PKD.
Clinical Manifestation
Main manifestations:

Edema (varying degrees) is the common symptom

Local edema: edema in face , around eyes
( Periorbital swelling) , in lower extremities.

Generalized edema (anasarca), edema in

penis and scrotum.

Non-specific symptoms:
▪Fatigue and lethargy
▪Loss of appetite, nausea and vomiting
▪Abdominal pain , diarrhea
▪Body weight increase
▪Urine output decrease
▪Peural effusion (respiratory distress)
 Laboratory Findings
Urine analysis Microscopy
Proteinuria : 3-4 + selective •Fat bodies
Hematuria (25% transient
24 urine collection for protein microscopic)
•Large number of hyaline
>40 mg/m2/hour cast
>50 mg/kg/day
>1 gr/m2/day

Spot urine specimen

Albumin/creatinine 200/400 mg/mmol
Urine Protein/Creatinine >0.2 mg/mg
Volume: oliguria (during stage of edema
formation)
idrar miktarının az olması
 Laboratory Findings
Plasma
Total protein 
Albumin   (<2.5 gr/dl)
Albumin/globulin 
Kolesterol
Urea and creatinine: usually normal
Compleman 3 :normal
Sedimentation rate 
 MCD-Treatment

• Prednisone tablets at a dose of 60 mg/m 2/day

(maximum daily dose, 80 mg divided into 2-3 doses) for
at least 4 consecutive weeks.

• After complete absence of proteinuria, prednisone dose

should be tapered to 40 mg/m 2/day given every other
day as a single morning dose.

• The alternate-day dose is then slowly tapered and

discontinued over the next 2-3 mo.
 MCD-Prognosis

•Usually responds to steroid and

immunosuppressive therapy
• Does not lead to renal failure
• May cause problems with frequent
relapses
 Well-organized Cell-matrix
extracellular matrix adhesion /
Specialiced cell interaction
contacts

Many of these functions and involved

molecules are not unique to the kidney!
Energy
supply Syndromal forms of SRNS Transcriptional
programming
STEROIDE DİRENÇLİ NEFROTİK SENDROM
 Focal Segmental
Glomerulosclerosis
•Mesangial matrix expansion with loss of normal glomerular
structures

•FSGS and MCD are podocyte diseases (podocytopathies)

•20% nephrotic syndrome in children and 40% in adults

• Second most common in children

• May present with only proteinuria

• Usually leads to progressive renal failure

Causes of FSGS
Pediatr Nephrol (2011) 26:1001–
1015
Pathogenesis
 Etiologies of CongenitalNephrotic syndrome
(0-3 Months of age)
Genetic: congenital NS of the Finnish Type (mutation in nephrin (NPHS1) gene
Autosomal recessive FSGS (mutation in podosin (NPHS2) gene
Autosomal dominant diffuse mesangial Sclerosis ((mutation WT1) gene
Congenital nephrotic syndrome ( mutation in laminin 2 gene)

Syndromes: Denys-Drash syndrome(mutation WT1) gene with DMS

Galloway Mowat syndrome
Nail patella syndrome
Cockayne syndrome
İdiopathic: Minimal change nephrotic syndrome
FSGS
Infections: Congenital syphilis
Congenital cytomegalovirus
Congenital toxoplasmosis
Finnish type (CNF)
Autosomal recessive inheritence
The gene for NPHS1 (NPHS1 gene) which codes nephrin
protein has been localized to chromosome 19q13

The classic findings include :

▪Prematurity,
▪Large placenta
▪Heavy proteinuria, which already begins in utero
▪Hypoproteinemia, edema

Currently, children with NPHS1 are successfully treated with

active protein and nutritional support, followed by bilateral
nephrectomy and dialysis, and finally, by renal transplantation