1. Nephrotic syndrome Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

2. Minimal-Change disease (MCD)
The most frequent cause of the nephrotic syndrome in children
Normal appearance by light microscopy but:
diffuse effacement of podocyte foot processes when viewed with
the electron microscope
Most common between the ages of 1 and 7 years
…but can develop at any age
Pathogenesis in human is still unknown

3. MCD, morphology On light microscopy:
-The cells of the proximal convoluted tubules
often are heavily laden with protein droplets
and lipids
-GBM is normal…even under EM
On electron microscopy:
…uniform and diffuse effacement of the foot
processes of the podocytes

4. MCD, also on EM: The podocytes also show: -vacuolization
-microvillous formation
-occasional focal detachments
…the changes are reversible by steroids, and the proteinuria remits

5. MCD, clinical course Insidious development of nephrotic syndrome
no hypertension
renal function is preserved
Usually: the loss is confined to small proteins (chiefly albumin)
… = selective proteinuria
Prognosis is good
More than 90% of children respond to a short course of corticosteroid
therapy

6. MCD, clinical course…cont’d
Proteinuria recurs in more than two thirds of the initial responders
…some of whom become steroid-dependent
Less than 5% develop chronic kidney disease after 25 years
…mostly due to focal and segmental glomerulosclerosis not detected
by biopsy
In adults: the response is slower & the relapse is more common

7. Focal segmental glomerulosclerosis (FSGS)
Focal + segmental sclerosis of glomeruli
Primary (idiopathic)…20-30%...not uncommon cause of nephrotic syndrome in adults &
children or
Secondary to:
-HIV (HIV nephropathy)
-Heroin abuse (heroin nephropathy)
-As a secondary event in other forms of glomerulonephritis
-As a maladaptation to nephron loss
-Inherited/congenital:
…mutations in cytoskeletal proteins and podocin
…Africans: polymorphism in in the apolipoprotein L1 gene (APOL1) on chromosome 22

8. FSGS, pathogenesis
Injury to the podocytes is thought to represent the initiating event of primary FSGS
Some believe that MCD and FSGS are part of a continuum
Entrapment of plasma proteins and lipids in foci of injury where sclerosis
develops…appear as hyaline masses in the glomeruli
IgM and complement proteins are commonly seen in the lesion
…also may be nonspecific entrapment
Recurrence of proteinuria and subsequent FSGS in a renal transplant in some
patients who had FSGS may occur (sometimes within 24 hours of transplantation)

9. FSGS, morphology Initially:
EM: effacement of foot processes
IF: nonspecific entrapment of IgM & complement in the affected segments
FSGS, morphology
Initially:
…focal and initially (in primary FSGS): mainly in
juxtamedullary glomeruli
…then all levels of the cortex
…some tufts of the glomerulus and sparing the other
tufts (segmental)
…increased mesangial matrix, obliterated capillary
lumina, and deposition of hyaline masses (hyalinosis)
and lipid droplets
Advanced disease (like other GNs):
Global sclerosis, tubular atrophy & interstitial fibrosis
A variant called: collapsing variant:
-idiopathic or due to HIV or other causes
-collapsed tufts with proliferation of podocytes …bad prognosis

10. Membranous nephropathy
An endogenous podocyte antigen, the phospholipase A2 receptor, is the antigen that is most often recognized by the causative autoantibodies
Slowly progressive
Mostly between 30 & 60 years old
Immune complex-mediated…in situ
Characterized by: subepithelial deposits
…which will cause: diffuse thickening of the capillary wall
…may not appear early in disease by LM
85% of the cases: caused by autoantibodies against podocyte antigens
…= primary

11. Membranous nephropathy, 15% are secondary
planted

12. Membranous nephropathy, morphology
Absence of inflammatory cells
Membranous nephropathy, morphology
Diffuse thickening of the capillary wall…the main feature
The subepithelial deposits are separated from each other by small, spikelike protrusions of GBM matrix that form in reaction to the deposits
= spike and dome pattern
Later in the disease, the
incorporated deposits may be
broken down and eventually
disappear, leaving cavities within
the GBM
Also there is effacement of podocyte foot processes
IF: capillary granular pattern

13. Membranous nephropathy, clinical course
Mostly as full-blown nephrotic syndrome
…other individuals may have lesser degrees of proteinuria
The proteinuria is nonselective, with urinary loss of globulins as well as smaller albumin molecules
The proteinuria does not usually respond to corticosteroid therapy
Secondary causes should be ruled out
Only about 40% suffer progressive disease terminating in renal failure after 2 to 20 years
An additional 10% to 30% have a more benign course with partial or complete remission of proteinuria

14. Membranoproliferative Glomerulonephritis (MPGN) and Dense Deposit Disease
Alterations in the GBM and mesangium + by proliferation of glomerular
cells
Accounts for 5% to 10% of cases of idiopathic nephrotic syndrome in children and
adults
Some: -only hematuria or non-nephrotic proteinuria
-combined nephrotic nephritic picture
Previously: MPGN I & II
…now: 2 separate entities: MPGN I & dense deposit disease
80%

15. MPGN I, notes about pathogenesis
As we said: mainly circulating complexes, but unknown antigen
…?may be also planted
…it also may occur secondarily: -Hepatitis B or C
-SLE
-Extrarenal infections
thought to be associated with many so-called idiopathic cases

16. Dense deposit disease, pathogenesis
Hypocomplementemia…due to consumption
of C3 and less
production from liver
Less clear
Excessive complement activation
…some patients have autoantibody against C3 convertase
…= C3 nephritic factor…it stabilizes C3 convertase
activation of alternative pathway (by uncontrolled C3 cleavage)
…other patients: factor H mutations or autoantibodies against factor H
It is still not clear how the complement abnormality induces the glomerular
changes

17. MPGN I & dense deposit disease, morphology
The glomeruli are large
Accentuated lobular appearance
Proliferation of mesangial and endothelial cells as well as infiltrating leukocytes
The GBM is thickened
The glomerular capillary wall often shows a double contour, or “tram track,” appearance, especially evident with use of silver or periodic acid–Schiff (PAS) stains
This “splitting” of the GBM is due to extension of processes of mesangial and inflammatory cells into the peripheral capillary loops and deposition of mesangial matrix

18. MPGN I & dense deposit disease, EM & IF findings
…characterized by discrete subendothelial electron-dense deposits on EM
…IF: C3, IgG, C1q, & C4…granular capillary
Dense deposit disease:
…EM: the lamina densa and the subendothelial space of the GBM are transformed into an
irregular, ribbon-like, extremely electron-dense structure, resulting from the deposition of
material of unknown composition
…IF: C3: capillary and mesangial…special patterns: segmental linear and ring patterns
… IgG and the early components of the classical complement pathway (C1q and C4) are
usually absent

19. MPGN I & dense deposit disease, clinical features
50%: as nephrotic syndrome
MPGN I: poor prognosis
Dense deposit disease:
…worse
…tend to recur more frequently in renal transplant
Forty percent progressed to end-stage renal failure, 30% had variable degrees of renal insufficiency, and the remaining 30% had persistent nephrotic syndrome without renal failure

20. Thank You