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Nephrotic syndrome

basic defect: increased permeability of glomeruli to plasma proteins

--> hypercoagulability, sepsis


Nephrotic Syndrome in Children

** serious bacterial infections especially with encapsulated bacteria

Increased risk of thromboembolic complications:
Pulmonary embolism / renal vein thrombosis

(Decreased antithrombin III, protein S, plasminogen
Increased fibrinogen, factors V and VIII)


Nephrotic Syndrome (NS)Basic Mechanisms

By definition: grater than 20-fold increase in loss of protein due to diffuse changes in the glomeruli
GBM becomes leaky to proteins, esp. albumin
No hematuria


a common place for Nephrotic edema:

Periorbital edema in the early morning common, resolves during the day under the influence of gravity.


Minimal Change Disease Nephrotic Syndrome

edema, hypoalbuminemia and hyperlipidemia
Risk of infection (particularly children)
Risk of thrombosis
Effacement of foot processes of podocytes (by electron microscopy)
Must rule out focal segmental glomerulosclerosis (sampling error)


Minimal Change Nephrotic Syndrome--Children

Massive proteinuria -->Edema in days to weeks
Dramatic response to corticosteroid therapy (Children>adults)
Long-term prognosis is generally good


Steroid Resistant Nephrotic Syndrome

Approximately 10 to 20 percent of children with nephrotic syndrome will fail to respond to initial steroid treatment

Some -due to single gene mutations (eg nephrin, podocin) that affect glomerular podocyte differentiation and function. (frequently present first year of life)


Minimal Change Nephrotic SyndromeAdults

Accounts for 10 to 25% of nephrotic syndrome in adults

80-95% of adults respond to steroid therapy
50 to 75% of responsive adults will have a relapse
Frequent relapses occur in 10 to 25%
25% of adults will be steroid dependent


Minimal Change Nephrotic Syndrome: ultrastructural changes

damaged visceral epithelial cells (podocytes)--> proteinuria.

primary visceral epithelial cell (podocyte) injury and loss of glomerular polyanions (defect in charge barrier--> proteinuria)


Edema Associated with Nephrotic Syndrome

Underfill hypothesis Hypovolemia, as a consequence of reduced plasma oncotic pressure, signals the kidney to retain the filtered sodium and water

Overfill hypothesis
Primary sodium retention is directly induced by the renal disease

the ability to tolerate diuretic therapy distinguishes:

Diuretics are well tolerated in patients with renal sodium retention (Overfill hypothesis)

But, if underfilling is the primary mechanism, diuretics --> worsening hypovolemia as evidenced clinically by an elevation in serum creatinine.


Key Facts for Minimal Change Disease

most common cause of nephrotic syndrome in children aged 2-12 years

histologically normal appearing glomeruli and corticosteroid responsiveness

Electron microscopy shows effacement of podocyte foot processes probably secondary to podocyte injury

Some steroid-resistant cases are due to single gene mutations


Membranous Nephropathy percentages

85% Nephrotic proteinuria associated with edema, hypoalbuminemia and hyperlipidemia
Risk of thrombosis
15% Nephritic- hematuria and hypertension
One of the most common causes of nephrotic syndrome in nondiabetic adults
75% of cases are primary (Anti-phospholipase A2)
25% are secondary
Lupus, infectious, malignancy, drugs, toxins, autoimmune


Membranous nephropathy: primary vs secondary

Characterized by diffuse thickening of the glomerular capillary wall
with little or no cellular proliferation (no hypercellularity)
Autoimmune disease linked to certain HLA alleles such as HLA-DQ A1 and antibodies to renal auto-antigens
Phospholipase A2 - frequent autoantigen in adults
Immune complex glomerular disease with subepithelial deposits (IgG, C) beneath podocytes on the subepithelial surface of the glomerular capillary wall


Membranous Nephropathy- Primary (85%)

Non-selective proteinuria

Pathologic diagnosis made in patients with proteinuria, immune deposits, GBM thickening without associated hypercellularity * and inflammatory change

C5b-C9 membrane attack complex (sublytic concentrations) causes inflammatory damage and protein leakage

Podocyte antigens: anti-PLA2


Membranous Nephropathy- Secondary (25%)

Planted antigens may be responsible for immune deposition in class V (membranous) lupus nephritis and hepatitis B virus (HBV)– associated membranous nephropathy.

Non-steroidal anti-inflammatory drugs

Malignancy (lung, colon,)

The resolution of secondary membranous nephropathy depends on remission of the immune response, the extent of podocyte damage, and expansion of the GBM.

The hallmark lesions of membranous nephropathy on electron microscopy are subepithelial electron-dense deposits on the outer aspect of the GBM, effacement of the foot processes of the overlying podocyte, and expansion of the GBM by deposition of new extracellular matrix between the deposits (which are the "spikes" seen with special stains).

Immunofluorescence microscopy reveals a diffuse granular pattern of IgG and C3 staining along the GBM


Immunofluorescence in membranous nephropathy

Glomerulus with diffuse, finely granular deposition of IgG along outer surface of all capillary walls.

The antibody is believed to represent autoantibody directed at some constituent of the podocyte membrane- PLA2


Electron microscopy in membranous nephropathy

Diffuse, granular immune complex deposits along outer surface of the capillary wall

Small extensions of BM between deposits (black arrows) = spikes by light microscopy


Focal Segmental Glomerular SclerosisFSGS

a histologic pattern of glomerular disease that occurs in a primary form of unknown cause and a secondary form associated with many other conditions
Focal --> Some but not all glomeruli are affected
Segmental --> Affected glomeruli are only partially involved

Most patients with primary FSGS present with either asymptomatic proteinuria or full nephrotic syndrome

Edema is the most common manifestation of FSGS

FSGS one of the most common causes of idiopathic nephrotic syndrome in adults


Primary FSGS

Primary FSGS is a clinicopathologic diagnosis.

requires a glomerular lesion --> FSGS

No evidence of an antecedent glomerulonephritis

No evidence of a systemic disease with glomerular involvement

No evidence of evidence of glomerular immune complex deposition

African American patients 4x as likely to have FSGS as similar white patients

Pathogenesis of primary FSGS remains unknown

Familial form shows mutations in slit diaphragm and podocyte proteins responsible for filtration barrier (nephrin, podocin)


Primary FSGS Clinical Course

Little tendency for spontaneous remission

Recurrences are seen in 25 – 50% of patients receiving allografts

(Long course (> 6 months) treatment with corticosteroids can induce remission in 40 – 80% of patients)

Rapidly recurs in transplanted kidneys
Nephrotic syndrome recurs soon after transplantation, often within 24 hours of engraftment and renal biopsy show no histologic evidence of FSGS

EM microscopy demonstrates variable foot process effacement after transplant

Patients appear to be deficient in serum factors that are necessary for the maintenance of normal podocyte function. (preliminary data)

Mature podocyte is a non-dividing cell which imply finite number of podocytes per glomerulus --> susceptible injury --> FSGS


Secondary FSGS

Secondary FSGS often presents with non-nephrotic proteinuria

Important to distinguish secondary from primary FSGS since treatment is different (Corticosteroids vs angiotensin inhibition)
- Secondary FSGS, inhibition of angiotensin-converting enzyme may slow or modify the disease course.
- Primary FSGS potentially treatable and curable (steroids/immunosuppressive)

Morphologic variant (collapsing glomerulopathy) typically associated with HIV-associated nephropathy  
These patients often have rapidly progressive renal failure and optimal therapy is uncertain


Causes of secondary FSGS

Virus Associated
(Heroin, Interferon, anabolic steroids)
Reduced nephron mass
(Solitary kidney, reflux nephropathy, systemic hypertension, sickle cell anemia)

These injuries promote altered cell signaling, reorganization of the actin cytoskeleton, and resulting foot process effacement


Glomerular Diseases that Commonly Cause Nephrotic Syndrome

Minimal change disease (most common children)
Focal segmental glomerulosclerosis (most common adults)
Diffuse membranous glomerulopathy

Membranoproliferative glomerulonephritis
1/3 nephrotic, 1/3 nephritic, 1/5 chronic progressive GN