Glomerular Diseases

Pathogenesis of glomerular diseases

Primary glomerulonephritis/ glomerulopathy
kidney is the only or predominant organ involved
Antibody mediated
Cell mediated

Secondary glomerular diseases

 Pathogenesis of glomerular diseases
Antibody-associated injury
Antibodies react in-situ within the glomerulus
(intrinsic or planted antigens)
Circulating antigen-antibody complexes
Cytotoxic antibodies
Mesangial / Endothelial / Visceral epithelial
Cell-mediated injury
Alternative C pathway activation
In-situ immune complex formation
In-situ immune complex formation
Anti-GBM antibody-induced nephritis
Antigens are normal components of the GBM
Bind the entire length of the BM
Diffuse, linear staining pattern
Antibodies may cross-react with other basement
membranes
Goodpasture syndrome
Fewer than 5%
Crescentic GN
In-situ immune complex formation
Anti-GBM antibody-induced nephritis
Antigens are normal components of the GBM
Bind the entire length of the BM
Diffuse, linear staining pattern
Antibodies may cross-react with other basement
membranes
E.g. Goodpasture syndrome
Fewer than 5%
Rapidly progressive glomerulonephritis
In-situ immune complex formation
Heymann nephritis
Similar to membranous glomerulopathy
Antibody reacts with antigens localized on the
basal surface of the visceral epithelial cells
Antigens not identified in humans
In-situ immune complex formation
In-situ immune complex formation

Antibodies against planted antigens

Granular staining, similar to the pattern in
circulating immune complex nephritis
Circulating immune complexes
 Pathogenesis of glomerular diseases
Mediators of glomerular injury
 Outcome of immunologic glomerular injury
depends on several factors, including
the initial severity of renal damage,
the nature and persistence of the antigens
the immune status, age, and genetic
predisposition of the host
 Morphology of glomerular injury
Hypercellularity
Cellular proliferation, Leukocytic infiltration,or
formation of crescents
Basement membrane thickening
deposition of amorphous electrondense material,
most often immune complexes
thickening of the basement membrane proper,eg.DM
Hyalinization and sclerosis

Diffuse Vs focal
Global Vs segmental
 Nephritic syndrome hypoalbumin-
proteinuria
emia
hematuria proteinuria

hyperlipid-
edema
emia
azotemia edema

lipiduria

hypertension
Nephrotic syndrome
Acute nephritic syndrome

hematuria

oliguria

hypertension
 Acute nephritic syndrome

Hematuria
Red cell casts in urine
Azotemia
Mild to moderate hypertension
Proteinuria and edema - mild
 Acute nephritic syndrome
Acute proliferative GN
Diffuse proliferation of glomerular cells &
associated with influx of leukocytes
typically caused by immune complexes
inciting antigen may be exogenous or
endogenous
Prototype
Poststreptococcal GN
Acute nephritic syndrome
 Acute nephritic syndrome
Poststreptococcal GN
1 4 weeks following a streptococcal pharyngitis
or impetigo
Group A-hemolytic streptococci type 12, 4, 1
Children > adults
Evidences
Elevated titers of antibody against streptococcal
antigens
Low serum complement levels
 Acute nephritic syndrome
Immune complex mediated GN
 Acute nephritic syndrome

Subepithelial hump
Acute nephritic syndrome

Diffuse
Hypercellular
Acute nephritic syndrome
Clinical course
- In the classic case, a young child abruptly
develops malaise, fever, nausea, oliguria &
hematuria (smoky or cocoa-colored urine) 1 to
2 wks after recovery from sore throat. The
patients exhibit red cell casts in the urine, mild
proteinuria, periorbital edema & mild to
moderate hypertension
- Important laboratory findings include
Elevations of antistreptococcal antibody (ASO)
titers
Red blood cell casts in urine
Elevation of BUN & serum creatinine
 Acute nephritic syndrome

Normal PSGN chronic GN

>95% <1%
RPGN
NB : In adults, the disease is less benign!
 Acute nephritic syndrome
Postinfectious GN
Bacterial infections
Staphylococcal endocarditis
Pneumococcal pneumonia
Meningococcemia
Parasitic infections
Malaria
Toxoplasmosis
 Acute nephritic syndrome
Postinfectious GN
Viral infections
HBV
HCV
Mumps
HIV
Endogenous
SLE
 Rapidly progressive glomerulonephritis
a syndrome associated with severe glomerular injury and
does not denote a specific etiologic form of
glomerulonephritis
Loss of renal function in a few days or weeks
Oliguria
Microscopic hematuria
Dysmorphic red blood cells and red blood cell casts in the
urine sediment
Mild to moderate proteinuria
Rapidly progressive glomerulonephritis
Morphologic correlate

Crescentic GN
proliferation of the parietal epithelial cells + infiltration of monocytes and macrophages
Primary renal/ systemic
Rapidly progressive glomerulonephritis
Type I RPGN (Anti-GBM disease)
, Goodpasture syndrome
Type II RPGN( Immune Complex)
Postinfectious ,SLE
Type III (Pauci-Immune)
ANCA associated
RPGN usually associated with systemic vasculitis
syndromes (without significant immune deposits)
Rapidly progressive glomerulonephritis
Type I
Goodpasture
Type II
Postinfectious, SLE, IgA nephropathy
Type III
Wegeners, PAN
Idiopathic cases
 Clinical manifestation
- Renal manifestation such as hematuria, moderate
proteinuria, HTN & edema occur
- Other clinical features depend on the specific
cause,eg.hemoptysis
- In the absence of treatment , progression to
irreversible renal failure can occur in matter of
weeks
 Nephritic syndrome hypoalbumin-
proteinuria
emia
hematuria proteinuria

hyperlipid-
edema
emia
azotemia edema

lipiduria

hypertension
Nephrotic syndrome
 The nephrotic syndrome
Massive proteinuria
3.5g/day
Hypoalbuminemia
<3g/dL
Generalized edema
Hyperlipidemia
Lipiduria
 The nephrotic syndrome
Susceptibility to infections
Staphylococci, pneumococci
Thrombotic and thromboembolic events
Renal vein thrombosis
loss of anticoagulant factors (e.g., antithrombin III)
Minority hematuria and mild hypertension
 The nephrotic syndrome
Primary glomerular Systemic diseases
diseases Diabetes mellitus
Membranous Amyloidosis
glomerulopathy Systemic lupus
Minimal change disease erythematosus
Focal segmental Drugs
glomerulosclerosis Infections
Membranoproliferative Malignancies
GN
IgA nephropathy
 Membranous glomerulopathy
most common cause of the nephrotic syndrome in adults
characterized by diffuse thickening of the glomerular
capillary wall
accumulation of electron-dense, immunoglobulin-containing
deposits along the subepithelial side of the basement membrane
Idiopathic (85%) or
Secondary
Drugs,infections,SLE,Tumors
Immune-complex mediated
Similar to Heymann nephritis
direct action of C5b-C9why leaky?
 Membranous glomerulopathy
IF
Granular deposits Igs and complement
EM
Irregular dense deposits between BM & epithelial cells
LM
Uniform, diffuse thickening of the glomerular capillary
wall
Proximal tubules protein reabsorption droplets
Membranous glomerulopathy
 Membranous glomerulopathy
- course of the disease is variable
- NB: R/o secondary couses first
- Proteinuria is non selective & does not usually
respond to corticosteroid therapy
- Although proteinuria persists in more than 60% of
patients, only 10% die or progress to renal failure
- Concurrent sclerosis of glomeruli in the renal biopsy
at the time of diagnosis is a predictor of worse
prognosis
- Eventually up to 40% - renal insufficiency
 Minimal change disease
Most common cause of nephrotic sxx in
childrem
2-6years
Pathogenesis immune
Association with immunization & URTIs
Response to immunosuppressive therapy
Association with atopic disorders
Association with certain HLA haplotypes
Prognosis
<5% develop CRF after prolonged follow up
 Minimal change disease
The principal lesion is in the visceral epithelial cells,
which show a uniform and diffuse effacement of foot
processes
The cells of the proximal tubules are often laden with
lipid and protein=lipoid nephrosis
 Despite massive proteinuria, renal function remains
good, and there is commonly no hypertension or
hematuria.
The proteinuria usually is highly selective, most of the
protein consisting of albumin
Most children (more than 90%) with minimal change
disease respond rapidly to corticosteroid therapy
However, the nephrotic phase may recur, and some
patients may become steroid dependent or resistant
Nevertheless, the long-term prognosis for patients is
excellent, and even steroid-dependent disease resolves
when children reach puberty
Minimal change disease
Minimal change disease
 Membranoproliferative GN
characterized histologically by alterations in the
basement membrane, proliferation of glomerular
cells, and leukocyte infiltration
Aka Mesangioproliferative GN
Young age
Nephrotic syndrome / (+) nephritic component/
non-nephrotic range proteinuria or proteinuria
 Morphology
glomeruli have a "lobular" appearance
accentuated by the proliferating mesangial cells
and increased mesangial matrix
"duplication" of the basement membrane
a "double-contour" or "tram-track" appearance
Membranoproliferative GN
 Membranoproliferative GN
Primary MPGN
Type I
Subendothelial deposits
Granular pattern C3, IgG
Type II
Dense-deposit disease
Thickened BM
Irregular linear or granular foci C3
Messangial rings (C3)
 Secondary MPGN
invariably type I
more common in adults
arises in the following settings:
Chronic immune complex disorders
SLE; hepatitis B infection; hepatitis C infection
1-Antitrypsin deficiency
Malignant diseases
chronic lymphocytic leukemia and lymphoma
 Membranoproliferative GN
Prognosis
Slowly progressive - ~50% CRF within 10 years
Minority spontaneous remission
High incidence of recurrence in transplant recipients,
particularly in dense-deposit disease
Dense deposits may recur in 90% of such patients,
although renal failure in the allograft is much less
common
 IgA nephropathy (Berger disease)
Young adults and children
Following infection
Respiratory tract
Recurrent Gross hematuria/ microscopic hematuria
proteinuria / acute nephritic syndrome
Most common type of glomerulonephritis worldwide
Prognosis
Slow progression to CRF
Extent of glomerulosclerosis shows correlation with
prognosis
 IgA nephropathy (Berger disease)
Elevated serum IgA
Genetic predisposition
Associations
Celiac disease
Liver disease
Mesangial immune complex deposition
 IgA nephropathy (Berger disease)
Normal/mesangioproliferative GN/ focal
proliferative GN/ crescentic GN
Immunofluorescence IgA
EM electron-dense deposits in the
mesangium
 IgA nephropathy (Berger disease)
Prognosis
Slow progression to CRF in ~25%
Extent of glomerulosclerosis shows correlation
with prognosis
 HEREDITARY SYNDROMES OF ISOLATED HEMATURIA
Alport Syndrome
Thin Basement Membrane Disease (Benign Familial
Hematuria)
 The nephrotic syndrome
Focal segmental glomerulosclerosis (FSGS)
Focal and Segmental Glomerulosclerosis (FSGS)
Often associated with the nephrotic syndrome
Primary/idiopathic(10% and 35% of cases of nephrotic
syndrome in children and adults resp)
Focal segmental glomerulosclerosis (FSGS) occurs in
the following settings
HIV infection (HIV nephropathy), heroin addiction (heroin
nephropathy), sickle cell disease, and massive obesity
adaptive response to loss of renal tissue
Complication of GN (IgA nephropathy)
Hyperfiltration after nephron loss
Focal and Segmental Glomerulosclerosis (FSGS)

Renal mass

Blood flow, filtration, transcapillary P

Cell injury

Leakage of proteins, inflammatory infiltrate,

mesangial cell proliferation
 Focal and Segmental Glomerulosclerosis (FSGS)
Often associated with the nephrotic syndrome

Primary/idiopathic
Complication of GN (IgA nephropathy)
Hyperfiltration after nephron loss
Inherited forms resulting from mutations affecting cytoskeletal or
related proteins e.g., nephrin
Secondary
HIV nephropathy, heroin nephropathy
Focal and Segmental Glomerulosclerosis (FSGS)
Initially affects only the juxtamedullary glomeruli
Later more generalized, global sclerosis
Nonspecific trapping of immunoglobulins and
complement components
IgM
Effacement of foot processes
? MCD
Focal and Segmental Glomerulosclerosis (FSGS)
Vs MCD
Higher incidence of hematuria and hypertension
Nonselective proteinuria
Response to corticosteroid therapy
Poorer prognosis
At least 50% of individuals with FSGS develop
end-stage renal failure within 10 years of
diagnosis
Focal and Segmental Glomerulosclerosis (FSGS)
Collapsing glomerulopathy
Sclerosis and collapse of the entire glomerulus
Proliferation of glomerular visceral epithelial cells
Associated prominent tubular injury focal
dilatations - microcysts
Characteristic lesion of HIV associated nephropathy
Poor prognosis
ARF/acute interstitial nephritis
Postinfectious GN
Thrombotic microangiopathies