Nephrotic syndrome

Proteinuria
 

content
 

Proteinuria :    Definition ,Types  and Causes.

                                                           
Nephrotic syndrome :
      Definition
      Historical perspective
      Epidemiology
      Clinical classification
      Histological classification
      Pathogenesis
      Pathophysiology of edema   
      Types & Causes
      Clinical approach (history , examination &
Laboratory evaluation )
      Treatment
       Complication
       Prognosis
 

Proteinuria
 

Normal urinary protein excretion

is approximately 150mg/day in
adults, Urinary protein excretion
is, variable in younger children
 

Normal 24-hour urinary

protein excretion by age
 

                                         Total urinary protein

excreted (mg)
Premature babies                    14–60
Full-term babies                     15–68
Infants                                     17–85
Children:
2–4 years                                20–121
4–10 years                              26–194
10–16 years                            29–238
 

Types of proteinuria
 

 
   1- Glomerular Proteinuria.
  2- Tubular Proteinuria.
  3- Overflow Proteinuria.
 

Causes of proteinuria
 

Artifactual
Infections
• Non-sexually transmitted
• Sexually transmitted diseases
Foreign body
Menstrual blood contamination
Glomerular diseases
• Nephrotic syndrome
• Glomerulonephritis
 
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Tubular diseases – inherited

• Cystinosis
• Wilsons disease
Tubular diseases – acquired
• Interstitial nephritis
• Reflux nephropathy
• Acute tubular necrosis
• Heavy metal poisoning
Non-pathologic Proteinuria
• Orthostatic Proteinuria
• Fever
• Exercise
 

Nephrotic syndrome
 

 
 Nephrotic syndrome is among the most
common types of kidney diseases seen
in children.
Definition:
It is characterized by massive proteinuria,
hypoalbuminemia, and edema, additional
clinical features such as hyperlipidemia are
usually also present.
 

Historical perspective
 

Definitions and clinical

classification
 

Nephrotic syndrome
 The diagnosis of nephrotic syndrome requires
the presence of edema,  severe proteinuria (>
40 mg/m2/hr or a protein: creatinine ratio    >
2.0), hypoalbuminemia (< 2.5 g/dl), and
hyperlipidemia.
Remission of nephrotic syndrome:
Remission represents a marked
reduction in proteinuria
(to < 4 mg/m2/h, or urine albumin
dipstick of 0 to trace for 3 consecutive
days) in association with resolution of
edema.
 

Relapse of nephrotic
syndrome
 
 Relapse of nephrotic syndrome is
defined as recurrence of severe
proteinuria (> 40 mg/m2/h, or urine
albumin dipstick ≥ 2 + on 3 successive
days), often with a recurrence of
edema.
Steroid-sensitive nephrotic syndrome:
Patients who enter remission in
response to corticosteroid treatment
alone are referred to as having steroid-
responsive or steroid-sensitive
nephrotic syndrome (SSNS).
 

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Steroid-resistant nephrotic
syndrome
 
 Patients with nephrotic syndrome who fail to
develop remission after 8 weeks of
corticosteroid treatment are referred to as
having steroid-resistant nephrotic syndrome
(SRNS).
Steroid-dependent nephrotic
syndrome
Some patients respond to initial steroid
treatment by developing complete remission,
but develop a relapse either while still
receiving steroids, or within 2 weeks of
discontinuation of treatment following a
steroid taperand are therefore
referred to as having steroid-dependent
nephrotic syndrome (SDNS)
 

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Frequently relapsing nephrotic

syndrome
 

If patients develop 4 or more episodes of

nephrotic syndrome in any 12-month period,
they are referred to as having frequently
relapsing nephrotic syndrome (FRNS)
Infrequently relapsing nephrotic syndrome:
episodes of nephrotic syndrome < 4 times per
12-month period.
 

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Epidemiology
 

The annual incidence of nephrotic

syndrome = 2 to 7 new cases per 100
000 children.
The prevalence is about 16 cases per
100 000 children, boys are twice as
likely to develop nephrotic syndrome as
girls, but by adolescence and adults
 such  incidence equal among males and
females.
 

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Pathogenesis of primary 
nephrotic syndrome
 

passage of protein molecules through

the glomerular Electrical charge is an
important determining factor for the
filtration barrier. Several reports have
indicated a reduction in the negative
charge of the GBM in nephrotic
syndrome                                .
.                      
Several morphologic changes in
podocytes in nephrotic syndrome were
include cell swelling; retraction and
effacement of the podocyte foot
 processes, resulting in the formation of
a diffuse cytoplasmic sheet along the
GBM;. The structural alterations in
podocytes often associated with
detachment from the underlying GBM,
have been shown to result in
Proteinuria                         .        
.                      
 

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Figure 1 
Electron micrograph :    showing a filtration slit with
adjacent 
podocytes P1 and P2; double-layered slit diaphragm
bridges between the two podocytes, and the glomerular
basement membrane (GBM).
 

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Minimal change nephrotic

syndrome
 

Several reports have indicated

qualitative and quantitative
abnormalities in both the humoral
(uncertain) and cellular immune
systems in MCNS (support).
Abnormalities in the cell-mediated
immune system have long been
implicated in the pathogenesis of
MCNS
 

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Focal segmental
glomerulosclerosis
 

The pathogenesis of primary FSGS

can be separated into four
categories:
• podocyte injury
• genetic mutations
• soluble mediators
• hemodynamic factors.
 

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Pathophysiology of edema 
 

Edema is the dominant clinical

manifestation of nephrotic syndrome in
children.
 
 Edema, a state of total body water and
sodium excess, is the result of fluid
accumulation in the interstitial space.
 

The pathogenesis of edema in nephrotic

syndrome due to:
         Hypoalbuminemia
         Impaired sodium and water
excretion
 

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causes of  
syndrome in children
 

A-Primary causes
1-Minimal change nephrotic syndrome
(MCNS)
 2-Focal segmental glomerulosclerosis
(FSGS)
3-Membranoproliferative
glomerulonephritis
4-mesangiocapillary
glomerulonephritis:  
   MPGN type I, II, III
5-Membranous nephropathy (MN)
 

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Secondary causes
 

Systemic diseases associated with NS :

• Henoch–Schönlein purpura
• Systemic lupus erythematosus
• Diabetes mellitus
Infectious diseases associated with NS:
• Hepatitis B (usually associated with MN, rarely MPGN)
• Hepatitis C (usually associated with MPGN)
• HIV (often with collapsing variant of FSGS)
Hematology/oncology:
 • Leukemia

• Lymphoma (Hodgkin disease usually MCNS)

  Sickle cell anemia
Drugs:
• Non-steroidal anti-inflammatory drugs (MCNS)
• Gold Penicillamine
• Captopril
Others:
• Bee stings (MCNS)
• Food allergies
• Obesity (usually with FSGS)
 

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Clinical approach
 

Clinical history:
While primary glomerulopathies
are usually responsible for
childhood nephrotic syndrome,
 The review of systems should
focus on extra renal symptoms that
may uncover secondary causes of
nephrotic syndrome.
review of medication exposure is
also crucial.
 

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Physical examination
 

Hypertension can be seen in

children with nephrotic syndrome,
but it is more often seen with
histologic lesions other than
MCNS.
Periorbital edema, ascites, and
peripheral
 edema are also expected findings
in nephrotic syndrome.
 

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Laboratory evaluation
 

  Establish the diagnosis of Proteinuria

by a dipstick            urinalysis. The
presence of a 3–4+ (300–2000 mg/dl    
for protein in the presence of edema
establishes a          preliminary
diagnosis nephrotic
syndrome                   
 

Proteinuria can be quantified by

obtaining urine            
protein/creatinine ratio in a spot urine
sample, and hypoalbuminemia and
 hypercholesterolemia should be 
confirmed                                
.                                                                
                                                                 
      
 

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 Mild azotemia is not unusual according

to ISKDC.
  ↑ serum creatinine in:  
       - 32%  with MCNS.
       - 41% of children with FSGS.
       - 50% of those with MPGN.
Macroscopic hematuria is unusual if
present should raise the suspicion of
renal vein thrombosis but microscopic
hematuria
  is not unusual seen in
        - 23% of children with MCNS.
       - 48% with FSGS
       - 59% with MPGN
 

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Hypocomplementemia ↓C3 complement in:

    - MPGN
    - SLE
     - PAGN.
 

Serology: hepatitis B surface antigen

and hepatitis B core antibody, hepatitis
C antibody, and HIV antibody.
 

Renal ultrasound is not necessary, but if

child with nephrotic syndrome who
develops gross hematuria,  USS should
 be done to exclude the possible
development of renal vein thrombosis.
 

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Consideration of renal
biopsy
 

Some indicated as age-based, with those > 10

years undergoing a biopsy because of the
higher likelihood of finding a histological
lesion other than
MCNS.                                                               
 
 

Others suggest a need for renal biopsy in only

those with clinical or serologic suspicion for
underlying Glomerulonephritis                 
                 
Most pediatric nephrologists consider
performing a diagnostic renal biopsy in all
 children with
SRNS                                                   
                                                  
To establish ‘a baseline’ histologic picture
before transitioning a child with nephrotic
syndrome to an immunosuppressive agent
with significant nephrotoxic risks                  
.                                                         
 

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Treatment
 

Corticosteroids have been the

mainstay of therapy for nephrotic
syndrome.
 
Steroid sensitivity has been reported in
89% of children with nephrotic
syndrome. Approximately 95–98% of
 children with MCNS are steroid-
sensitive, compared with only 20% of
those with FSGS                             
 

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Steroid-sensitive nephrotic
syndrome
 

                         
The most widely used protocol for the initial
episode treatment of the childhood nephrotic
syndrome :
prednisone  60 mg/m2/day (or 2 mg/kg/day up
to a maximum
of 80 mg/day) in divided doses for 6 weeks,
followed by taper to 40 mg/m2/day (or 1.5
mg/kg/day up to a maximum of 60 mg/day)
alternate-day single dose  for the next 6 weeks.
The alternate-day oral steroids should be
 gradually tapered off over approximately 6
weeks (~0.25 mg/kg/dose/week until
off).                                 
 

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Steroid-dependent and
frequently 
relapsing nephrotic syndrome
 

The majority of children with nephrotic

syndrome develop one or more relapses of the
disease. These relapses may be transient, with
spontaneous remission occurring within 4–14
days in some. Despite prolonged initial steroid
use, about 40–50% of those with complete
remission of nephrotic syndrome subsequently
develop either frequent relapses or steroid-
dependence.
 
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Factors associated with ↑

risk 
for relapses of nephrotic
syndrome
 

  1- Children who present at < 5 years

of age.
   2- Boys.
   3- Intercurrent infections, 70% of
relapses have            been reported to be
preceded by URTI.
 

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Management of frequent
relapses
 

Prednisone at 2mg/kg/day divided

dose /(40–60 mg/m2/day) until the urine is
protein-free for 3–4 consecutive days,
followed by taper to 1.5 mg/kg/day
every other morning for 2-4 weeks, and
then gradual taper by 0.25mg/kg/dose
every 2 weeks until reaching the lowest
alternate-day dose which kept that child
in remission (usually10–20 mg/dose, or 15–
20 mg/m2/dose).    
This ‘prophylactic’ dosage can the  be
continued for  from 6 to 18 months, and
then tapered by 0.25 mg/kg/dose every 2
weeks until discontinuation of
therapy.                                                    
                    
 

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 Steroid-sparing agents
 

Many frequently relapsing and steroid-

dependent children either fail to have an
adequate response or develop clinically
significant side effects of steroid    
therapy                                                     
                                                                 
                   
Alternative treatments are include:
   Cyclophosphamide
   Chlorambucil .
   Cyclosporine
   Levamisole
   more recently mycophenolate mofetil.
 

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Alkylating agents
 

 1-Cyclophosphamide (2 mg/kg/day for 8–12

weeks).
2- Chlorambucil (0.2 mg/kg/day for 8–12
weeks).
 

Both agents induce long-term remissions in

~75% of children        with FRNS, and less
effective in  children with SDNS, with     long-
term remissions seen in only 30–35% of
children.           
     
Both of these cytotoxic agents associated
toxicity:                            - Leukopenia(~33%)
   - Hair loss (2–18%)
   - Thrombocytopenia (2–6%)
   - Severe bacterial infections (1.5–6.3%),
   - Malignancies (0.2–0.6%),
   - Seizures (3.4% – chlorambucil only)
   - Hemorrhagic cystitis 2.2% –cyclophosphamide
only, also gonadal                     toxicity in males)
 

 
 

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Cyclosporine A
 

Dose (5–6 mg/kg/day for 9 months and

tapered off over 3 months)
Side effects:  
     - Hypertension.
      - Mild ↑  in serum creatinine
      - Hyperkalemia,
      - Gingival overgrowth 
      - Hypertrichosis. 
      -Nephrotoxicity (interstitial fibrosis).
 

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Levamisole
 
 Dose (2.5mg/kg on alternate days for 6
months), reported to prolong the duration of 
remissions and to have steroid-sparing effects
in children with both FRNS and SDNS.
 

Side effects are minimal, include :

       - Flu-like symptoms
       - Neutropenia,
       - Agranulocytosis
       - Erythematous rash
       - Vomiting seizures
        - Hyperactivity
 

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Mycophenolate mofetil and

mizoribine (MMF)
 

Dose used for MMF 600 mg/m2/dose given

twice daily
 Side effects of MMF include :
        - Nausea, Vomiting
        - Diarrhea,
        - Constipation,
        - Headache,
        - Edema,                
        - Bone marrow suppression
        -Gastrointestinal bleeding
        -Hyperuricemia .
Based on the above findings MMF is
increasingly being recognized as a safe and
effective alternative, agent in the management
of children with FRNS and SDNS
 

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Management of SRNS can be
divided into four major categories
 

 • General care medical

  • supportive therapy
• immunosuppressive therapy
• immunostimulatory therapy
[Levamisole]
• non-immunosuppressive therapy.
[ACE inhibitors]
 

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General care medical

 

- Identification and treatment of

suspected thrombosis.
- Identification and treatment of
suspected infection.
- Maintenance or restoration of
intravascular volume
- Maintenance of adequate protein intake
(130–140% of RDA)
 

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Supportive and adjunctive

therapies
 

1- Dietary adjustments. 
2- Alteration of immunizations.
3- Management of edema :
           Avoidance of excessive fluid intake
           Moderate restriction of dietary salt.
           Diuretics (only for severe edema)
           Severe anasarca : intravenous 25%
albumin infusion
           1 g/kg/dose, given over 3–4 hours,
followed  by
           furosemide challenge (1–2
mg/kg/dose).
 

 
 
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4- Management of
hyperlipidemia
 

-  Avoidance of high fat intake

- Regular exercise regimen (30–45 minutes of
moderately
   intense exercise daily) 
- Use of HMG CoA reductase inhibitors
(statins)
- LDL apheresis
 

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Pulse intravenous
methylprednisolone
 

IV methylprednisolone (30 mg/kg) in

the following schedule:
 Alternate days for 2 weeks,
then weekly for 8 weeks,
then every other week for 8 weeks,
then monthly for 9 months,
then every other month for 6 months.
This treatment was accompanied by
oral prednisone, and if needed,
cyclophosphamide or chlorambucil
 

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Side effects
 

  -  Cataracts (22%).
  - Impaired growth (17%).
  - Hypertension (17%).
  - Leukopenia  (19%).
   - Gastrointestinal distress which
was common.
 

42

 
 
 
Non-immunosuppressive therapy.
[ACE inhibitors] 
 
 

Angiotensin-converting enzyme
inhibitors (ACEIs)
increasingly used in the management of
SRNS.
Low-dose (0.2 mg/kg/day)
High-dose (0.6 mg/kg/day).
 The antiproteinuric effect of this class
have multiple  factors:
    ↓ transcapillary hydraulic pressure.
    ↓ glomerular capillary plasma flow
rate.
     Alteration in the permselectivity of
the glomerular                filtration
barrier
 

43

Side effects ACEIs

 

  1-Transient acute renal failure.

  2- Cough.
  3- Hypotension
 
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Complications nephrotic
syndrome  
 

(1) Infection:   Risk factors:

  - Low IgG levels Impaired T-lymphocyte)
  -  Impaired tissue perfusion due to edema
  -  Low factor B (C3 proactivator) levels
(↓bacterial opsonization
  -  Low factor D levels (decreased bacterial
opsonization)
  -  Immunosuppression due to corticosteroid
and other agents
 

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Clinical presentation of infections in
nephrotic syndrome
 

- Cellulitis (most often due to

Staphylococcus)
- Peritonitis (most often due to
Pneumococcus
- Sepsis.
 

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(2) Acute renal failure

 

Possible explanations for this

include:
    - renal vein thrombosis.
    - ↓ renal perfusion.
    - Acute tubular necrosis.
     - Interstitial edema within the renal
parenchymal bed.
    - Alterations in glomerular
permeability.
 

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(3) Thromboembolism 
 

 Risk factors :
1- Intravascular volume depletion (results ↑
blood viscosity)
2-Decreased coagulation inhibitors
(antithrombin III)
3 -Decreased plasminogen, increased α2-
antiplasmin
4- Hyperlipidemia
Clinical presentation
      Deep venous thrombosis
       Inferior vena cava thrombosis
      Renal vein/artery thrombosis
 

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(4) Anemia
 

Chronic nephrotic syndrome can also lead to

the development of anemia due to :
    Loss of both erythropoietin & transferrin
into the urine.
   ↓ serum half-life for erythropoietin.
   ↑ transferrin catabolism
 

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Endocrine
(5)
abnormalities
 
 Loss of multiple binding proteins for
hormones into the urine:
1- vitamin D-binding protein:
       - Low levels of 1,25-
dihydroxycholecalciferol D3
       - Modest hyperparathyroidism
       - Hypocalcemia.
2- Binding proteins for
corticosteroid and thyroxine
 

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 (6) Deficiencies of both copper and

zinc.
 

    - Decreased serum copper :

         due to loss of ceruloplasmin in the
urine.
 
      - Decreased zinc levels :
      due to loss of zinc into the urine
attached to albumin.                 
 

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(7) Corticosteroids treatment-related

side effect  
 

  - Growth impairment
  - Bone demineralization
  - Cataract
  - Hpertension
   - Avascular necrosis of the femoral
head.
 

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Prognosis of nephrotic
syndrome
 

• It is generally accepted that the initial

response to corticosteroids          (i.e. induction
of complete remission) is the single
best                  indicator of the long-term
prognosis for a child presenting             with
nephrotic syndrome.                       
.                                                                
• children who fail to respond to an 8 week
course of oral                         corticosteroids
have a guarded prognosis. 
 

• Non-responsiveness to corticosteroids clearly

identifies as patients    at high risk for
progressive kidney disease and
subsequently           progressed to ESRD.
 

 
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• overall steroid responsiveness was seen in

78% of newly diagnosed      children treated
with corticosteroids, the likelihood of
achieving          remission varied greatly by
histological diagnosis    
 

Steroid responsiveness:
   - 93% for MCNS.
   - 30% for FSGS.
   - 56% for mesangial
proliferativeglomerulonephritis,
   - 7% for MPGN
   - 0% for membranous nephropathy. 
 

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Relapse rate 
 

 • Relapses of nephrotic syndrome

occur commonly in            SSNS.
• Only 30% patients with SSNS will
never experience a           relapse,
although the overall tendency to
relapse              decreases with time.
 

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Concluding remarks
 

Nephrotic syndrome is among the most

common forms of
kidney disease seen in children. It
continues to be a problem for pediatric
nephrologists, as neither the
pathogenesis nor the mechanism of
 action of the drug proven effective in
treating it have yet been fully defined.
 
    Despite this, unless children with
nephrotic syndrome    
develop resistance to corticosteroid
therapy the long-term   prognosis is
generally
excellent.                                                 
 

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    SRNS children remain unresponsive

to even the newest and most effective
therapies that have been attempted,
leaving them at increased risk for both
ESRD and death.
 

    Further research on both the

pathogenesis and the mechanism of
 action of effective therapies for
nephrotic syndrome is needed to permit
the development of more effective and
less-toxic therapies for this very
common childhood kidney disease
 

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