Download Kidney disease Terminology

Renal pathology: Nephrotic
and Nephritic Syndromes
John Higgins
Learning Objectives
Morphology of renal injury
 Mechanisms of glomerular injury and clinicopathologic correlations of
prototype disease with a typical clinical presentation
◦ Nephrotic syndrome (minimal change nephrotic syndrome)
◦ Nephritic syndrome (Post streptococcal GN)
◦ RPGN (anti-GBM disease)
◦ Asymptomatic hematuria/Proteinuria (IgA nephropathy)
◦ Systemic disease (Lupus nephritis)

Medical renal pathology
overview

Glomeruli
◦ Glomerulonephritis
◦ Diabetes
◦ Amyloidosis

e.g. Crescentic glomerulonephritis
Medical renal pathology
overview

Tubules
◦ Acute tubular necrosis
◦ Pyelonephritis
◦ Myeloma kidney

e.g. Acute tubular necrosis
Medical renal pathology
overview

Interstitium
◦ Acute or chronic
interstitial nephritis

e.g. Tubulointerstitial nephritis
Medical renal pathology
overview

Blood vessels
◦ Classic polyarteritis
nodosa
◦ Malignant hypertension
◦ Atheroemboli

e.g. Necrotizing arteritis
Points not to be
overlooked
Tubulointerstitial diseases (such as ATN and pyelonephritis) and
vascular diseases (such as arteriolonephrosclerosis due to
hypertension) are more common than glomerular diseases
 Of the glomerular diseases, diabetes is much more common than
glomerulonephritis
 Nevertheless, we’re going to talk about rare glomerular diseases
for the rest of this lecture

Medical kidney disease –
New problems (why renal is hard)

Clinicopathologic correlation
◦ Clinical features
◦ Morphology
◦ Disease names

Immunofluorescence and EM
◦ Glomerular immune complex diseases

New terminology
Practice
translating
between
light, IF,
EM
Kidney Disease
Terminology
Proliferation – more cells than normal
 Necrosis
 Sclerosis
 Deposits

Normal:
H&E
Endothelial
cells
Mesangial
cells
Visceral epithelial
cells (podocytes)
Normal:
PAS
Endothelial
cells
Mesangial
cells
Visceral epithelial
cells (podocytes)
Mesangial proliferation
Increase in the number of cells in the
mesangium to four or more per zone
 As in mesangioproliferative
glomerulonephritis such as IgA

Mesangial
proliferation
Epithelial proliferation
(Crescent formation)
Increase in parietal epithelial cells together
with infiltrating leukocytes
 Often associated with fibrinoid necrosis
 50% or more glomeruli with crescents
defines crescentic glomerulonephritis

Cellular
crescent
Bowman’s
capsule
Capillary
tuft
Crescent
Necrosis

Deposition of fibrin (fibrinoid necrosis)
and/or karyorrhectic fragments
Fibrinoid
necrosis
Residual
capillary tuft
Fibrin
Bowman’s
capsule
Crescent
Sclerosis

Absolute or relative increase in the amount
of extracellular matrix
◦ Mesangial matrix increase
◦ Partial or complete capillary tuft collapse
Mesangial
sclerosis
Diabetic
glomerulopathy
Thickened
GBM
Mesangial
cells
Mesangial
matrix
Segmental
sclerosis/
hyalinosis
Sclerosed
segment
Residual
normal tuft
Global
glomerulo
sclerosis
Deposits –
Immune complex


Location
◦
◦
◦
◦
Mesangial
Subendothelial
Subepithelial
Intramembranous
Quality (by immunofluorescence)
◦ Granular
◦ Linear
Subepithelial
deposits
Epithelial cell
cytoplasm
GBM
Deposits
Subendothelial
deposits
GBM
Endothelial cell
cytoplasm
Subendothelial
deposit
Intramembranous
deposit
GBM replaced by electron
dense deposit
Mesangial
deposit
Deposit
Mesangial
cells
GBM
Linear deposits
IgG and C3 that outline the glomerular
basement membrane
 Not visible by EM
 Seen in the setting of crescentic
glomerulonephritis
 Characteristic of Goodpasture’s disease
(anti-glomerular basement membrane
disease)

Linear IgG by IF
Seen with glomerular crescents: antiGBM nephritis
Granular IgG by IF
Mesangial
deposits of
IgA: Don’t
look as
much like a
glomerulus
Distribution of glomerular lesions
Diffuse – involving >50% of the glomeruli
 Global – involving and entire glomerulus
 Focal – involving <50% of the glomeruli
 Segmental – involving only a portion of a
single glomerulus

Renal glomerular syndromes
corresponding glomerular pathology

Nephritic (bleeding)
◦ Increased cellularity
 Mesangial
 Crescents
◦ Necrosis
◦ Immune complex deposits in the
mesangium and subendothelial
space
◦ Linear glomerular basement
membrane deposits

Nephrotic (heavy proteinuria)
◦ Podocyte injury
 Foot process fusion
 Subepithelial immune complex
deposits
 Segmental glomerular basement
membrane collapse
Nephrotic syndrome
causes

Children
◦
◦

Primary diseases (95%)

Membranous (5%)

Minimal change (65%)

FSGS (10%)

MPGN (10%)

Other proliferative GN (10%)

Notice that:
◦
Secondary causes are rare in children
but common in adults
◦
Secondary causes may resemble the
primary lesions (e.g. malignancy
associated membranous) or look
nothing like them (e.g. amyloid)
◦
In children, the most common primary
lesion is minimal change nephrotic
syndrome. Because this is steroid
responsive, children with NS are
treated empirically
Secondary (5%)

SLE, drugs, Infections, malignancy, hereditary nephritis, beesting allergy
Adults
◦
Primary diseases (60%)

Membranous (30%)

Minimal change (10%)

FSGS (35%)

MPGN (10%)

Other proliferative GN (15%)
◦
Secondary diseases (40%)

Diabetes, amyloidosis, SLE, drugs (gold, penicillamine, heroin),
Infections (malaria, syphilis, hep. B, HIV), malignancy, bee-sting
allergy
Minimal change nephrotic syndrome
Epithelial
cell foot
process
effacement
Focal Segmental Glomerulo Sclerosis (FSGS)
Non-specific
trapping of plasma
proteins
Segmental
sclerosis
Loss of
capillary
lumens
with
foam
cells
Membranous glomerulopathy
Capillary wall
thickening only if
deposits are big
enough
Diffuse
subepithelial
deposits
Granular loop
deposits of IgG
always present but
not specific
Conditions associated with
membranous nephropathy






Primary/idiopathic
◦ most have antibodies against podocyte antigen
Phospholipase A2 receptor (PLA2R)
Malignancy: solid tumors
Infection: hepatitis B/C, malaria, syphilis
Drugs: penicillamine, gold
Autoimmune diseases: SLE
Sarcoidosis
Membranoproliferative
Glomerulonephritis (MPGN) (type I)
Mesangial and
endocapillary
proliferation
with lobular
accentuation
and double
contoured
capillary walls
Diabetic glomerulosclerosis
Visible by
light
microscopy
only if
advanced
enough
GBM
thickening
and
mesangial
matrix
increase
Amyloidosis
Amorphous
material by
light
microscopy
Haphazardly
arranged
10nm fibrils
Commonly light chain
- associated with
myeloma but does not
have to be
Amyloidosis:
Congo red stain under polarized light
Clinical manifestations of
glomerular disease






Nephrotic syndrome
Acute nephritic syndrome: Post
Streptococcal GN
Rapidly progressive renal failure (RPGN)
Asymptomatic hematuria and/or
proteinuria
Systemic Disease
Chronic renal failure
Acute Post-Infectious GN
Group A  hemolytic streptococci (types
12,4,1) eg. pharyngitis, impetigo
 Staphylococcus (eg. subacute bacterial endocarditis, deep

seated abscesses, infected ventriculo-atrial shunts);
pneumococcus, meningococcus
 Viral infections: Hep B, C, HIV, varicella
 Parasitic infections: malaria, toxoplasmosis
Acute Post-Streptococcal GN
Renal symptoms 1-4 weeks after
streptococcal throat or skin infection
 >> ASO titers, low serum complement
levels
 Atypical clinical presentation and
course prompt a renal biopsy in
children

Diffuse, proliferative,
exudative
glomerulonephritis
Neutrophils in
capillary lumens
(acute exudate)
Red blood
cell casts
Granular C3, IgG
Glomerular
basement
membrane
Neutrophils
Deposits
Subepithelial “humps”
GBM
Epithelial
cell
“hump”-like
deposit
Acute Post-Streptococcal GN
Pathogenesis:
◦ Immune complex-mediated process
◦ the specific streptoccocal cationic
antigenic component responsible is
unclear (exogenous antigen)
◦ ? cationic planted antigen versus
circulating immune complexes
Acute Post-Streptococcal GN:
Outcome

Spontaneous resolution in 95%
of the children (& 60% of
adults)
◦ 1-2 % have crescents with rapid
deterioration of renal function
◦ 1-3 % develop slow progression to
chronic renal failure
Crescentic GN
subdivided into 3 categories, based on IF:
-anti-GBM disease : linear IgG & C3; no deposits by EM
-Immune complex-mediated : abundant deposits eg.
SLE, post-infectious GN, Henoch-Schönlein Purpura
-Pauci-Immune GN : No deposits by IF/EM
eg. Granulomatosis polyangiitis (Wegener’s),
microscopic polyangiitis
Anti-GBM disease
(Goodpasture’s syndrome)
Clinical presentation: RPGN
 If associated hemoptysis and dyspnea:
Goodpasture’s syndrome
 Pathogenesis: circulating auto-antibodies
against non-collagenous domain of 3 chain of
collagen type IV (cross reacting with glomerular
and alveolar basement membranes).

Glomeruli
Fibrinoid Necrosis
Glomerular
necrosis
Fibrin extravasation, cellular
crescent
Crescent
Normal
glomerular tuft
Fibrin
Linear IgG; No deposits
in EM
EM: No deposits
Alveolar hemorrhage
Blood
Alveolar septa
Anti-GBM disease: Clinical
Course




Steroids, cytotoxic agents and plasmapheresis :
Resolves pulmonary hemorrhages
Renal function improves if intervened early (sCr 45 mg/dl)
Irreversible renal failure if therapy is delayed
May recur in renal transplants (anti-GBM antibody
titers
monitored)
Clinical manifestations of
glomerular disease






Nephrotic syndrome
Acute nephritic syndrome
Rapidly progressive renal failure (RPGN)
Asymptomatic hematuria and/or proteinuria
◦ IgA nephropathy (Berger’s disease)
◦ Alport syndrome, Thin basement membrane disease
Systemic Disease
Chronic renal failure
IgA Nephropathy

Clinical presentation:
◦ Recurrent gross/microscopic hematuria
◦ Proteinuria usually non-nephrotic range
◦ No systemic disease (vs Henoch-Schönlein
Purpura)
◦ Acute nephritic syndrome in 5-10% of cases
◦ Hematuria often preceded by respiratory and
gastrointestinal infections
IgA Nephropathy

LM:
◦ mesangioproliferative most common
◦ endocapillary proliferative and/or sclerosing lesions may
be seen.
◦ Segmental crescents can be present.

IF: defining feature
◦ Dominant /co-dominant IgA stain (IgA /= IgG); C3, K, L +

EM: Mesangial deposits;  segmental subendothelial
deposits
Mesangial Proliferation
Expanded,
hypercellular
mesangium
Fibrocellular crescent
Less cellular,
“Fibrous”
areas
Crescent
Cellular areas
Mesangial IgA,
C3
Mesangial
deposits
GBM
Mesangial
immune
complex
Henoch-Schönlein Purpura
Most common in children (3-8 yrs), but also
occurs in adults
 Syndrome: systemic vasculitis
◦ Purpuric skin rash (extensor surfaces of
extremeties)
◦ Abdominal pain, vomiting, melena
◦ Arthralgias
◦ Renal manifestations (IgA nephropathy)

Clinical manifestations of
glomerular disease

Nephrotic syndrome

Acute nephritic syndrome

Rapidly progressive renal failure (RPGN)

Asymptomatic hematuria and/or proteinuria

Systemic Disease:
◦ Systemic lupus erythematosus, Henoch-Schönlein Purpura, Goodpasture’s
syndrome, Wegener’s granulomatosis, cryoglobulinemic GN

Chronic renal failure
Systemic Lupus Erythematosus
Multisystem disease of autoimmune origin
 Predominantly seen in women of childbearing age (F:
M=9:1), > severe in AA, Hispanics
 Acute or insidious in onset; chronic remitting and
relapsing course
 Primary target organs: skin, joints, kidney, serosal
membranes

1997 Revised Criteria for SLE
Classification (4 required for diagnosis)
1.
Malar rash
8.
Neurological disorder
2.
Discoid rash
9.
Hematological disorder
3.
Photosensitivity
10.
Immunological disorder:
Anti-dsDNA
4.
Oral ulcers
Anti-Sm Ab
5.
Arthritis
Antiphospholipid Ab
6.
Serositis
7.
Renal disorder
11.
Antinuclear Ab (ANA)
Systemic Lupus
Erythematosus
Role of antibodies in the diagnosis:
◦ ANA is highly sensitive , but not very specific
◦ Anti-dsDNA and anti-Sm antibodies are less
sensitive but more specific
 Etiology and pathogenesis:
◦ Genetic factors
◦ Environmental factors eg. Drugs
◦ Immunological factors (dysregulation & loss of
self tolerance)

SLE and Kidney



The morphological changes in lupus
nephritis (LN) are extremely variable
The lesions result from deposition of
immune complexes (Ag-AB)
The clinical presentation, course and
prognosis of various lesions differ
◦ Nephrotic, nephritic-nephrotic, RPGN
Endocapillary
proliferation
Too many cells and loss of
capillary lumens
“Wire loops” (large
subendothelial
deposits)
Intraluminal hyaline
thrombi
Cellular crescent
Different case:
Membranous LN (nephrotic
syndrome)
Diffusely
thickened,
Lumpy-bumpy
capillary walls
IgG, IgM, IgA, C3,
C1q, K, L: “full
house”
Mesangial
deposits
Deposit
GBM
Subendothelial
deposits
Deposit
GBM
Deposit
Subepithelial
deposits
GBM
Deposits
Tubuloreticular
inclusions
CLASSIFICATION OF Lupus Nephritis
Class
I
LM
normal
IF
mesangial
II
mesangial
hypercellularity
focal proliferative GN
(< 50% glomeruli)
mesangial
mesangial
deposits
mesangial + capillary Mes + subendo
wall
dep
IV
diffuse proliferative (>
50% glomeruli)
mesangial + capillary Mes + subendo
wall
dep
V
Membranous
VI
Advanced sclerosis
III
capillary wall (+/mesangial)
+/-
EM
mesangial
deposits
Subepithelial
+/- mes
+/-
Chronic
Glomerulonephritis
Chronic end-stage damage to glomeruli, tubules and
blood vessels
 Bilateral kidneys symmetrically contracted
 Associated with hypertension
 Clinical features of chronic renal failure and uremia
develop

Globally
sclerosed
glomeruli
Atrophic
tubules
Atrophic
tubules
Robbins..