Transcript Nephritic Syndrome

Pathology of
Glomerular Disease II
Dr. Álvaro Barboza Quintana.
Clinico-pathologic Classification
in Renal Syndromes
H = High
frequency among patients with the syndrome
L = Low frequency among patients with the syndrome
1.
•Nephrotic Syndrome (NS)
•Primary Nephrotic Syndrome
•Minimal change disease - H
•Focal segmental glomerulosclerosis - H
•Membranous glomerulopathy - L
•Systemic Nephrotic Syndrome
•Diabetes mellitus - H
•Amyloidosis - L
•Systemic lupus erythematosus (WHO Class V)
2A
.
Nephritic Syndrome - Low Serum
Complement
Primary Nephritic Syndrome
•Post-infectious glomerulonephritis (GN)
•Membranoproliferative GN - L
Systemic Nephritic Syndrome
•Systemic lupus erythematosus (WHO Class III, WHO
Class IV) - H
•Infectious endocarditis
•HCV-associated cryoglobulinemia
2B. Nephritic Syndrome - Normal Serum Complement
Primary Nephritic Syndrome
•IgA Nephropathy
•Hereditary Nephritis (Alport syndrome) - L
•Rapidly progressive GN (RPGN), ANCA associated, pauciimmune
Systemic Nephritic Syndrome
•Lupus nephritis (WHO Class II) - H
•Anti-basement membrane disease (Goodpasture's Syndrome) - L
•Systemic vasculitis:
•Polyarteritis nodosa
•microscopic polyarteritis
•Wegener's granulomatosis
•Henoch Schoenlein Purpura
•Thrombotic thrombocytopenic purpura / Hemolytic uremic
syndrome
3 Acute Renal Failure
.
•Pre Renal - Decreased renal perfusion
•Renal
•Rapidly progressive GN (RPGN)
•Pauci-immune RPGN, ANCA-associated
•Anti-glomerular basement membrane disease
(Goodpasture) - L
•Immune complex mediated RPGN:Systemic lupus
erythematosus, IgANephropathy, etc.
•Acute tubulointerstitial diseases:
•Acute tubular necrosis (ATN) - H
•Acute interstitial nephritis (AIN) - H
•Post Renal - Obstruction
4
Chronic renal failure
.
Glomerular diseases
that run with
nephrotic syndrome.
Minimal Change Disease
(Lipoid Nephrosis)
Most frequent cause of nephrotic syndrome in
children (2 – 6 years of age).
 Follows a respiratory infection or routine
prophylactic immunization.
 “Its most characteristic feature is its
usually dramatic response to
corticosteroid therapy”
 Etiology: It’s not known, in most cases is
idophathic.

– Interstitial nephritis by medical treatment
– HIV, heroin
– Hodgkin disease
Morphology MCD
By light microscopy the glomeruli are
normal.
 By electron microscopy, the basement
membrane appears normal.
 Principal lesion: visceral epithelial cells
show a uniform, and diffuse effacement of
foot processes,
– “Fusion” of foot processes, represents
simplification of the epithelial cell
architecture with flatening, retraction
and swelling of foot processes.

Glomeruli are normal by light microscopy in minimal change disease, as shown
in this biopsy. The glomerular basement membrane is thin and delicate, and
mesangial cellularity and matrix are within normal limits. (Jones' silver stain,
X200).
In this electron micrograph, overlying epithelial cell foot processes are
effaced (giving the appearance of fusion) and run together.
Morphology MCD



This changes are reversible
after corticosteroid therapy
and remission of the
proteinuria.
The cells of the proximal
tubules are often laden with
lipid, reflecting tubular
reabsorotion of lipoproteins
passing through diseased
glomeruli: Lipoid nephrosis.
Immunofluorescence studies
show no immunoglobulin or
complement deposits.
Clinical Course

Nephrotic syndrome:
– Proteinuria (albumin) > 3.5 g/day.
– Hipoalbuminemia
– Edema
– Hyperlipidemia
– Lipiduria
– Thromboembolic events
– Slow decrease of the glomerular filtrate
Membranoproliferative Glomerulonephritis
(Mesangiocapillary glomerulonephritis)
5% to 10% of cases of idiopathic nephrotic sd. In
children and young adults (< 30 years).
 Associated with other systemic disorders and
known etiologic agents (secundary MPGN) or may
be primary, without known cause (idiopathic) in
the kidney.
 Primary MPGN

– Type I: Inmune complexes and activation of alternative
and classic pathways of complement
– Type II:Alternative pathway of complement.
Autoantibodies IgG (Nephritic factor C3) which joins with
C3 convertase and inactivate C3.
Morphology MPGN

By light microscopy, both types are similar.
– The glomeruli are large and hipercelular (by
proliferation of cells in the mesangium).
– The glomeruli have an “hyperlobular” appearance
accentuated by the proliferating mesangial cells
and increased mesangial matrix.
– The GBM is thickened in the peripheral capillary
loops.
– The glomerular capillary wall aften shows a
“double-contour” or “tram-track” appearance
(silver or PAS stains).
As seen here, the glomerulus has increased overall
cellularity, mainly mesangial.
Extensive double contours of the glomerular basement membranes, stained by
silver, in membranoproliferative glomerulonephritis type 1, caused by mesangial
interposition and new basement membrane formation in response to
subendothelial immune complex deposits. The deposits are PAS positive and
globular-to-sausage shaped (Jones' silver stain; original magnification, x400).
Type I MPGN
2/3 of cases
 “Subendothelial electrodense deposits”
under transmission electronic mycroscopy.
 Immnunofluorescence

– C3 in a granular pattern
– IgG
– Early complement components (C1q and C4).
Membranoproliferative glomerulonephritis type 1. The marked endocapillary proliferation
(proliferating endothelial and mesangial cells) appears to occlude the capillary lumen.
Numerous large subendothelial and occasional mesangial-dense immune complex-type
deposits (bottom middle) are present (transmission electron microscopy; original
magnification, x4,700
Segmental, coarsely granular-to-globular or elongated capillary
wall IgG deposits in membranoproliferative glomerulonephritis
type 1 (immunofluorescence with anti-IgG; origina magnification,
x200).
This electron micrograph demonstrates the dense deposits in the
basement membrane of MPGN type II. There are dark electron
dense deposits within the basement membrane that often
coalesce to form a ribbon-like mass of deposits.
Type I
Clinical Course: Massive proteinuria, Nephrotic sd.
 Treatment: Elimination of the infection.
 Prognosis: Good, 70 – 85% without clinical
alterations.

Type II
• Clinical Course: Nephrotic and Nephritic sd.
• Prognosis: Most patients progress to endstage renal disease within 10 years.
In both types: Hipocomplementemia, cause of
the comsumption in the glomeruli.
Membranous
Glomerulonephritis
Membranous Nephropathy
Epimembranous GN
Spikes GN
Membranous GN
Most common cause of nephrotic
syndrome in adults.
 Characterized by:

– Diffuse thickening of glomerular capillary wall
– Accumulation of electron-dense, deposits of
immunoglobulin.
– Along the subepithelial side of the basement
membrane
Membranous GN
Idiopathic – 85% of cases
 Secondary to:

– Drugs: penicillamine, captopril, gold,
NSAIDs
– Underlying malignant tumors: carcinoma of
lung, colon and melanoma.
– Systemic Lupus: Most common type.
– Infections: chronic hepatitis B/C, syphilis,
schistosomiasis, malaria.
– DM, thyroiditis.
•Early Stage: Glomeruli appear normal or exhibit
uniform, diffuse thickening of glomerular capillary wall.
•BM material is laid down between the deposits,
appearing as irregular spikes protruding from the
GBM (silver stain is the best)
IMMUNOFLUORESCENCE: Deposits of
immunoglobulines (G or M) and complement.
Electron microscopy: thickening by irregular dense deposits
between BM and podocites (subepithelial). Podocites have lost
their foot processes.
Clinical Course
Nephrotic syndrome or non-selective
proteinuria.
 Common symptoms: hematuria,
hypertension, and symptoms of
secondary causes.
 Course: irregular, indolent.
 As the glomeruli sclerosis progresses:
BUN elevated, hypertension and
reduction in severity of proteinuria.

Prognosis and Treatment

Prognosis:
– 60% recovers with persistent proteinuria
– 10% die or progress to renal insufficiency.
– Spontaneous remission and better prognosis
in women with non-nephrotic proteinuria.

Treatment:
– NON
Renal Amyloidosis
Amyloidosis
A systemic immune disease characterized by
deposition of amyloid (may be localized)
 Amyloid
is a pathologic proteinaceous
substance, deposited between cells in various
organs and tissues with a wide variety of
clinical settings.
 Tipically involves:

– Kidneys, spleen, liver, myocardium,
thyroid, pituitary and tongue.

adrenals,
Associated with:multiple myeloma, chronic
inflammatory conditions, chronic renal failure,
Alzheimer’s disease, type 2 diabetes.
Amyloidosis
Amyloid is formed by fibril proteins in 95%
and by glycloproteins (P component) in 5%.
 There are 15 biochemically distinct forms of
amyloid proteins:

–
–
–
–
Amyloid Light Chain
Amyloid –associated protein
Ab amyloid in Alzheimer’s disease
All produce the same consequences and give the
same pattern in microscopy.
Renal amyloidosis is the most common and
potentially the most serious form of organ
involvevement.
Gross Pathology
Kidneys may be
either :
(1)Enlarged, firm
with a waxy
appearance
(2)Shrunken and
contracted
owing
to
vascular
stenosis.
E
A
R
L
Y
S
T
A
G
E
Amyloid is deposited in the glomeruli, interstitium, arteries and arterioles. Appear as
irregular thickenings of mesangium and capillary basement membranes.
Congo Red Stain - Polarizing microscopy
Show diffuse amyloid deposition (green birefringence)
in glomerular tufts and mesangial regions.
END STAGE: Glomerular tufts are flooded and replaced by masses or
ribbons of amyloid.
Glomerular diseases that
run with Nephrytitc
Syndrome
Poststreptococcal
Glomerulonephritis
(Postinfectious Acute
Glomerulonephritis)
Pathogenesis

Secondary to a pharyngeal infección with
varying latent period

Nephritic syndrome
– Group A (1,2,3,4,12,18,25,49,55,57,60)
 Low complement levels, and high titles of streptococcal
products.

Glomeruli
– Granular immune deposits
– Endostreptsin and cationic antigens in afected áreas
Macro

Macroscopic hematuria with a rusty or smokey
hue.
Micro


Glomeruli: bloodless, hypercelular and
enlarged.
Proliferating mesangial and endothelial cells
oclude the capillary lumina
– PMN and monocyte infiltration.
 Exudative and difuse (will affect all the lobules)

Interstitium: edema
Electron Microscopy

Dome-shaped deposits projecting
outward from epithelial side of
basement membreane.
– Epithelial cell slit pores
– Separated from the basement
membrane by cearl zone continuos
with the lamina rara externa.

PMN and monocytes
Clinical Features

Spontaneous nefritic syndrome
– Fever, nausea, gross hematuria, oliguria after
recovery from pharyngitis.
Note: adults have a less spontaneous start with
HTA.
During epidemics, symptoms may be rare.
1% of children develop intense oliguria and
progresive glomerulonephritis.
 Outcome in adults is less favorable.

During sporadic cases, 60% have an early
recovery.

1 or more weeks.
Glomeruli show diffuse hypercellularity due to mesangial and endothelial
cell increase and a large number of polymorphonuclear neutrophils
(PMNs). H&E
Diffuse proliferative acute postinfectious glomerulonephritis with
numerous PMNs with PAS-positive cytoplasm and endocapillary
proliferation. PAS
The garland pattern of immune complexes due to large
subepithelial deposits in acute postinfectious
glomerulonephritis is shown (immunofluorescence
Hump-shaped deposits in
acute
postinfectious
glomerulonephritis
with extensive foot
process
effacement and
endocapillary
proliferation
Rapidly Progressive
Glomerulonephritis
Rapidly Progressive Glomerulonephritis
General Info

Very uncommon
– 2 % of all cases presenting with GN

Predominates in men (2:1)
– Young to middle aged
Rapidly Progressive Glomerulonephritis
Classification
 1.-
Post-infectious (Post-Streptococcal)
 2.- Associated to Systemic Diseases
 Lupus, Goodpasture syndrome, vasculitis,
Wegener
 3.-
Primary or idiopathic
In all cases the basic
pathogenic mechanism is
immunogenic
Rapidly Progressive Glomerulonephritis
Pathogenesis

The presence of fibrin in Bowman’s space
promotes the epithelial proliferation and
formation of crescents
Extravasation due
to capillary damage
Production stimulated
by factors liberated
by Monocytes
GLOMERULUS
Fibrin
Fibrin
Rapidly Progressive Glomerulonephritis
Microscopic and
Macroscopic Aspect
MACRO: pale hipertrophic kidneys with
petechial hemorrages on the cortical surface
 MICRO: proliferation of glomerular epithelial
cells and mononuclear infiltrate forming
crescents in the urinary space (Neutrophils and

linfocytes may also be found)

Crescents: complex mixture of proliferating epithelial cells and
infiltrating monocytes forming concentric layers around the
capillary tufts (which are compressed)

This is a case of RPGN due to Lupus
The implication of a cellular
crescent is that the glomerulus has
sustained acute intense injury.
IDIOPATHIC
RPGN
Rapidly Progressive
Glomerulonephritis
Pathogenesis of symptoms
Glomerular tufts adhere to
Bowman’s capsule
Cicatrization of capillaries
Renal
Failure
OLIGURIA
POST-GLOMERULAR
ISCHEMIA
TUBULAR ATROPHY
AND INTERSTITIAL
FIBROSIS
Electron Microscopy: damage to basal membrane with ruptures but
no evidence of immune complex deposition.
•The urinary space in the top of the photograph shows portion of a
crescent with the dark strands representing fibrin (arrow).
Immunofluorescence: positivity with antibody to
fibrinogen. With a rapidly progressive GN, the
glomerular damage is so severe that fibrinogen leaks into
Bowman's space, leading to proliferation of the epithelial
cells and formation of a crescent.
Rapidly Progressive
Glomerulonephritis
Clinical features

Extremely rapid deterioration of renal
function, within weeks or up to 2
months
– Acute nephritis (Nephritic Sd.) with acute renal
failure
– Hypertension and edema
– Hematuria, proteinuria, pyuria (nephrotic sd.)
– Oliguria or anuria
 The patient may refer a viral syndrome or
respiratory infection weeks before onset of renal
failure
Goodpasture’s Syndrome
(Anti-Basement Membrane Disease)
Goodpasture’s Syndrome
General Info

Acute and necrotizing RPGN associated to
pulmonary hemorraging and hemoptysis

Uncommon disease affecting primarily men (4:1)
between 20-30 years of age.

Autoimmune disease in which there is production of
Anti-Basement Membrane Antibodies (ABM) that
deposit on alveoli and glomeruli
Goodpasture’s Syndrome
Pathogenesis
The Goodpasture antigen resides in the noncollagen portion of the 3-alpha chain of type IV
collagen
 Precipitation factor is unknown, may be:

–
–
–
–
–


Virus
Hydrocarbonated solvents
Tobacco smoke (permissive role)
Drugs
Cancer
Genetic predisposition: DRW15/DQW6
The lesion consists of deposits of ABM antibody
and complement on the basement membrane of
glomeruli and alveoli causing their destruction
Goodpasture’s Syndrome
Macroscopic and
Microscopic Aspect
MACRO: same aspect as RPGN
 MICRO: crescents composed of epithelial cells and
monocytes surrounding capillary tufts in the
urinary space

– Methenamine silver stain
– Electron Microscopy: does not show deposits, only
architectural damage and epithelial proliferation
– Immunofluorescence

The lungs show alveolar hemorrage, hemosiderinfilled macrophages and thickening of alveolar septi.
The BM shows immune deposits
Silver stain
Immunofluorescence: shows positivity with
antibody to IgG has a smooth, diffuse, linear
pattern that is PATOGNOMONIC
Goodpasture’s Syndrome
Clinical features
Typically begins as flu-like illness with evidence of
pulmonary compromise
 Pulmonary hemorrages
HEMOPTYSIS
 Progressive dyspnea
 Nephritis (Nephritic Sd.) and acute renal failure
 The disease progresses rapidly with renal failure ocurring
within weeks or months

Treatment and Prognosis



High doses of steroids, with or without cytotoxic agents.
Plasmapheresis removes ABM-antibodies
Better prognosis than other diseases causing RPGN
Glomerulonephritis IgA
or
Of Berger
Classification
This form of glomerulonephritis is
characterized by the presence of
prominent IgA deposits in the mesangial
regions.
 Primary glomerular disease
 Frequent cause of recurrent hematuria
 Most common
 Present in children and young adults.

Pathogenesis
Genetic or acquired abnormality of inmune
regulation leading to increased mucosal IgA
synthesis in response to respiratory or GI
exposure to environmental agents.
 IgA1 and IgA1complexes are entrapped in
the mesanguim.
 They activate the alternative complement
pathway and initiate glomerular injury.

MICRO/ H&E




Mesangial widening or
proliferation (arrow)
Segmental proliferation
Overt crescentic
glomerulonephritis
(rare)
Sclerosis (healing of
focal proliferative
lesion).
MICRO/ Electron Mic.

Mesangial electron
dense deposits and
increased mesangial
matrix and cellularity
in IgA nephropathy
(transmission electron
microscopy, original
magnification
x8,500).
MICRO/ Immunofluorescence

Mesangial deposition of IgA
Clinical Course
Gross hematuria after GI or respiratory
infection.
 5-10% develop a typical acute nephritic
syndrome.
 Hematuria lasts several days and then
subsides, only to return every few months.

Sistemic Lupus
Erithematous
Diffuse Proliverative
Glomerulonephritis
Introduction

SLE-
Classic prototype of the multisystem disease of
autoimmune origin, characterized by a
bewildering array of autoantibodies,
particulary antinuclear antibodies (ANAs).
Acute or insidious in its onset, it is a chronic,
remitting and relapsing, often febrile illness
characterized principally by injury to the skin,
joints, kidney, and serosal membranes.
Classification
Lupus Glomerulonephritis
Kidney appears to be involved in 60 to 70% of cases.
According to the WHO (morphologic class.)
 Class I: Normal by light, electron, and
imunofluorescent microscopy
 Class II: Mesangial lupus glomerulonephritis
 Class III: focal proliferative glomerulonephritis
 Class IV: Diffuse proliferative
glomerulonephritis
 Class V: Membranous glomerulonephritis
MICRO/ H&E

Proliferation of mesangial cells and endothelial
cells, along with infiltrating mononuclear and
polymorphonuclear leukocytes afecting more
than 50% of the glomerular area.

Extensive peripheral capillary wall subendothelial
immune deposition (wire loop), and
extracapillary proliferation in the form of
crescents.

Fibrinoid necrosis, leukocyte infiltration, wireloop deposits, hyaline thrombi, and hematoxylin
bodies
MICRO/ Others

Half of the tuft is
distorted by marked
endocapillary
proliferation with
occasional infiltrating
cells. Segmental areas of
basement membrane
splitting and
eosinophilic
subendothelial deposits
and mesangial
eosinophilic deposits are
visualized (Jones' silver
stain; original
magnification x400).
Clinical Course

Typically have:
– high anti-DNA antibody titers
– low serum complement levels
– Very active urinary sediment with:
 erythrocytes
 other casts present on urinalysis
– Proteinuria
– Half of the patients will have nephrotic
syndrome
– Hypertension
¡ X FIN ¡
Gracias...
[email protected]
MMI