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WVSU-College of Medicine

WestVisayas State University Medical Center


Department of Pediatrics

NEPHROTIC AND
NEPHRITIC
SYNDROME
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GLOMERULAR STRUCTURE

The glomerulus consists of a network of capillaries invested by epithelium.


The glomerular capillary wall is the filtering area

Consists of four basic structure:


1. Thin layer of fenestrated endothelial cells.
2. Glomerular basement membrane (GBM)
3. Visceral epithelium: (podocytes)
4. Mesangial cells and mesangial matrix:

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ELECTRON MICROSCOPY

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LAYERS OF GLOMERULAR WALL
1. Thin layer of fenestrated 3. Visceral epithelium:
endothelial cells. (podocytes)
2. Glomerular basement  It shows a characteristic foot processes
(pedicles) embedded and adherent to
membrane (GBM): It GBM.
consists of  These foot processes are separated by
1. Collagen 20-30 nm filtration slit which are
bridged by a thin diaphragm composed
2. Laminin of nephrin molecules
3. Fibronectin  critical to maintain glomerular barrier
4. Other proteins function.

4.
Mesangial cells and
mesangial matrix:
 It serve as a support of glomerular tuft.
 These cells is capable for proliferation.
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GLOMERULAR FILTRATION
• 15% of glomerular
filtration through the
mesangium,
• 85% of glomerular
filtration through the
fenestrated epithelium

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GLOMERULAR FILTRATION
The major characteristic of glomerular filtration
are
1. High permeability to water and
small molecules
2. Almost impermeable to
molecules of the size of albumin
(70KD).
• The latter characteristic is called glomerular
barrier function,
• Discriminates among protein depending on
their size (the larger, the less permeable).

• Also the charge affect the permeability (The


more cationic the more permeable).

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PATHOGENESIS OF GLOMERULAR DISEASES
Immune mechanisms underlie
most cases of primary
glomerular diseases .
It may be
1. Antibody mediated
2. Cell mediated

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1. ANTIBODY MEDIATED GLOMERULAR INJURY:
Two forms are recognized:
A. Injury resulting from B. Injury by antibody
deposition of circulating reacting in situ within the
immune complexes. glomerulus
(IC)

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A. CIRCULATING IMMUNE COMPLEXES

The antigen may be


1. Endogenous as in SLE or
2. Exogenous as acute glomerulonephritis
follow certain bacteria (Streptococci) or viral
(HBV).

• Antigen antibody complexes are formed


in the circulation and then trapped in the
glomeruli, where they produce injury
through binding of complement .
• These IC are seen either by Electron
microscopy as dense deposits
• Immunofluorescence microscopy, as
granular deposits

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B. NEPHRITIS IN SITU
• The best example is anti glomerular
basement membrane disease.
• In this type antibody are directed
against fixed antigen in the GBM.
• Also can react to planted non-glomerular
antigens interacting with intrinsic
component (Heymann’s model)
• Some times the anti GBM antibodies
cross react with basement membrane of
alveoli resulting in simultaneous lung
and kidney disease (Good Pasture
syndrome).
• The antibody can be visualized along
GBM by indirect immunofluorescence
microscopy, giving a characteristic
linear pattern.

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2. CELL MEDIATED INJURY
• There is increasing evidence that sensitized T • 1- Complement-leukocyte mechanism:
cells can cause glomerular injury . Activation of complement Generation
of chemotactic factors (C5a) Attract
• These may be the case in some forms of
neutrophils 1. Produce Proteases which
rapidly progressive glomerulonephritis.
degrade GBM, 2. O2 free radicals which
• Glomerular damage is reflected cause tissue damage 3. Arachidonic acid
physiologically by loss of barrier function metabolites (as TXA2) and which lead to
manifested by proteinuria and reduction of GFR.
reduction of glomerular filtration rate (GFR).
• Endothelin & other vasoconstrictors also
• Many mechanisms are described: contribute to reduction of GFR.
Complement-leukocyte mechanism C5-9
• In addition GFR is also ↓ as a result of
complement components Cytotoxic
obstruction of glomerular lumen by 1.
antibodies Monocytes and macrophage.
infiltrating inflammatory cells and 2.
Platelets
proliferating mesangial cells.
• 2- C5-9 complement component: This
component causes epithelial damage. It
also up regulates the transforming growth
factor receptors on epithelial cells, and
• lead to excessive synthesis of extra
cellular matrix and GBM thickening. FIRST UP 11
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• 3- Cytotoxic antibodies: antibodies
directed against glomerular structure and
produce cytotoxicity (even if IC is absent)
• 4- Monocytes and macrophage: They
secrete a number of biologically active
mediators which contribute to glomerular
damage.
• 5- Platelet: It aggregates in the
glomerulus and release PG and growth
factors.
• Epithelial injury: is the most important
factor in glomerular damage.
• This can be induced by 1. Antibody to
visceral epithelium or by 2. Toxins or others.
• Such injury is reflected 1.
Morphologically by loss of foot processes 2.
Functionally by proteinuria.

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CONSULTANTS
NEPHROTIC
SYNDROME
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NEPHROTIC SYNDROME
refers to clinical condition that include five main features;
1. Massive proteinuria (more than 3.5 gm/day)
2. Hypo-albuminaemia (less than 3 gm/dl)
3. Generalized edema
4. Hyperlipidemia (increase cholesterol & triglycerides)
5. Lipiduria (Lipid casts in urine ).

At the onset renal function is normal (BUN, creatinine) but later


on it is impaired.

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PATHOGENESIS OF NEPHROTIC SYNDROME
The initial event is damage to capillary wall resulting in increase permeability to plasma
protein.
With long standing heavy proteinuria serum albumin tend to become depleted and
decreased.
The drop of osmotic pressure will lead to generalized edema
As fluid escape from vessels to tissues,
1. there is decrease of plasma volume with
2. compensatory secretion of aldosterone
3. resulting in salt and water retention and
4. further aggravate the edema.

Hypoalbuminemia trigger increased synthesis of lipids in the liver

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NEPHRITIC
SYNDROME
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NEPHRITIC SYNDROME
• It is a clinical complex usually of acute onset
characterized by five criteria:
1. Haematuria with diagnostic red cell casts.
2. Oliguria and impairment of kidney function
3. Hypertension
4. Mild proteinuria.
5. Mild edema (localized to face)

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PATHOGENESIS OF NEPHRITIC SYNDROME
GFR is decreased due to obstruction of glomerular lumen by
• The proliferating glomerular cells
• Infiltrating inflammatory cells
• Due to hemodynamic changes (vasoconstriction).

The inflammatory reactions injure the capillary wall and produce hematuria
Reduced GFR is manifested clinically by oliguria.
Hypertension is the result of both
1. Fluid retention and
2. Renin release from ischemic kidney.
Acute nephritic syndrome may be produced
1. Secondary to other disorders as SLE or
2. may as a result of Primary glomerular disease

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HENOCH SCHONLEIN PURPURA
systemic vasculitis – deposition of IgA in the
skin and kidneys

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TREATMENT
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STEROID-SENSITIVE NEPHROTIC SYNDROME
• Definitions of terms (Table 4), such as
nephrotic level albuminuria and
hypoalbuminemia, response to therapy, and
indications for renal biopsy, were
established.

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STEROID-SENSITIVE NEPHROTIC SYNDROME

Responder: Protein-free urine for >3 days during initial treatment


Infrequent relapser: Fewer than three relapses within 6 months of the initial
response or fewer than four relapses within any 12-month period
Frequent relapser: Three or more relapses within 6 months following initial
response or four relapses within any 12-month period
Steroid-dependent: Recurrence of proteinuria on alternate-day steroid therapy or
within 2 weeks after cessation of treatment
Steroid-resistant: Failure to respond to initial prednisone therapy or to 4 weeks of
daily prednisone for relapse

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Cumulative distribution of time to response for initial responders.

Roberto Gordillo, and Adrian Spitzer Pediatrics in Review


2009;30:94-105
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©2009 by American Academy of Pediatrics CONSULTANTS
TABLE 5. INDICATIONS FOR RENAL BIOPSY IN
NEPHROTIC SYNDROME

At Time of Diagnosis:
•Two or more of the following: Age >10 years
•Persistent or gross hematuria
•Hypertension
•Renal insufficiency
•Low C3 complement values
Subsequently:
•Persistent proteinuria (at the end of 4 weeks of daily prednisone therapy)

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CLINICAL FEATURES
• The hallmark of nephrotic syndrome is heavy proteinuria, and the most common presenting sign
is edema that becomes visible when fluid retention exceeds 3% to 5% of body weight. Usually,
edema appears initially in areas of low tissue resistance (ie, periorbital, scrotal, and labial
regions)

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Treatment of nephrotic syndrome.

Roberto Gordillo, and Adrian Spitzer Pediatrics in Review


2009;30:94-105
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©2009 by American Academy of Pediatrics CONSULTANTS
TREATMENT
• Prednisone is the drug of choice and should be started as soon as a presumptive diagnosis of
primary nephrotic syndrome has been made, and infection, including tuberculosis, has been ruled
out
• The treatment proposed by the ISKDC consisted of 60 mg/m2 BSA per day, calculated on the
basis of ideal weight for height (not to exceed 80 mg/day), divided in three doses.
• Daily administration was continued for 4 weeks, followed by 40 mg/m2 BSA per day, given as a
single dose in the morning, on alternate days, for an additional 4 weeks. Of the patients afflicted
with MCNS, about 90% responded to steroids, and of those, about 60% relapsed.

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RETROSPECTIVE ANALYSIS OF 389 CHILDREN
• n a retrospective analysis of 389 children included in the ISKDC studies who had MCNS, 80%
were in remission at 8 years.
• Absence of hematuria at presentation, remission within 7 to 9 days from the start of treatment,
and age older than 4 years have been reported to be predictive of few relapses.

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• A prolonged initial treatment with prednisone (6 weeks of daily followed by 6 weeks of
alternate-day administration) has been found to decrease the frequency of relapses.
• In a Cochrane Review of the subject, the authors concluded that the higher the relapse rate with 2
months of initial treatment, the greater the effect of subsequent prolonged administration of
prednisone.

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TREATMENT OF FREQUENT RELAPSERS
• Children who are frequent relapsers may benefit from an alkylating agent, such as
cyclophosphamide (2 mg/kg per day), generally given for 8 to 12 weeks
• A meta-analysis revealed that the relative risk of relapse in children who received this treatment
is reduced by 60%.
• The cumulative dose of cyclophosphamide should not exceed 200 mg/kg because of gonadal
toxicity.
• In a number of uncontrolled studies, cyclosporine has been reported to reduce the incidence of
relapses in 75% to 90% of patients who have steroid-dependent nephrotic syndrome. The drug
has serious adverse effects (hypertension, hyperkalemia, hypertrichosis, gingival hyperplasia)

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• Cyclosporine administration requires careful monitoring of serum concentrations and should be
undertaken only by experienced physicians. The frequency of relapses usually decreases with
time, becoming rare at or after puberty.
• Nonetheless, as many as 52% of patients have been reported to have at least one relapse during
adulthood.
• Pregnancy apparently is a predisposing factor. As long as the patient responds to steroid therapy,
the risk of progression toward renal insufficiency remains negligible.

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Actuarial remission rate after
treatment with cyclophosphamide in
steroid-dependent nephrotic
syndrome. Reprinted with permission
from Arch Dis Child.

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STEROID-RESISTANT NEPHROTIC SYNDROME
• Steroid-resistant nephrotic syndrome may occur at birth or during the first postnatal year, but is
more common after the age of 2 years.
• This group of patients represents no more than 10% of the entire population of children who have
nephrotic syndrome, but their prognosis usually is bleak.
• Their renal function deteriorates, and eventually they become candidates for dialysis or renal
transplantation

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• Nephrotic syndrome encompasses a diverse group of conditions that share the common
denominator of massive loss of protein in the urine. Progress in identifying the cause and
pathogenesis of each of these conditions has been slow. The current identification of various
forms of nephrotic syndrome is based primarily on histologic findings, which are not always
pathognomonic. Treatment has and still depends on drugs that lack specificity and have
numerous, often serious, adverse effects.
• The following conclusions are worth remembering:
• Most children who have nephrotic syndrome have MCNS, which is responsive to prednisone
therapy.
• Response to steroid therapy is the best prognostic indicator.

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• Most (∼60%) of children who have MCNS relapse, some of them frequently. Cyclophosphamide
and cyclosporine decrease the incidence of relapses.
• Compelling evidence suggests that renal biopsy should be performed at onset only in children
who, in addition to proteinuria, have macroscopic hematuria, hypertension, persistent renal
insufficiency, or low C3 complement values. Another indication is failure to respond to steroid
therapy (proteinuria still present at the end of 4 weeks of daily prednisone therapy).
• Most children who have nephrotic syndrome and fail to respond to steroids have FSGS. Most
alkylating agents are ineffective. Cyclosporine has been reported, in uncontrolled studies, to
induce remission in 20% to 50% of patients who failed to respond to steroids. The drug requires
monitoring of serum values and has serious adverse effects. Proteinuria recurs in most patients as
soon as the treatment is discontinued.
• Several genetic forms of FSGS, due to mutations that encode proteins at the level of the
podocytes, have been identified. They account for a small minority of patients who have
nephrotic syndrome, and none responds to treatment.
• Dialysis and transplantation have improved the long-term prognosis of patients who reach end-
stage renal disease, even infants who have CNS.
• Some glomerulopathies, such as FSGS, MPGN, and possibly CNS, may recur in renal
transplants. Treatment with immunosuppressive agents and plasmapheresis is effective in about
30% of such patients

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THANK YOU
April Hansson +1 23 987 6554

april@firstupconsultants.com

http://firstupconsultants.com

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