Transcript Document
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, pauci immune
Systemic Nephritic Syndrome
•
Lupus nephritis (WHO Class II) H
•Anti-basement membrane disease (Goodpasture's Syndrome) •Systemic vasculitis: •Polyarteritis nodosa •microscopic polyarteritis •Wegener's granulomatosis •Henoch Schoenlein Purpura •Thrombotic thrombocytopenic purpura / Hemolytic uremic
L
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 normal.
the glomeruli are 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 show no immunoglobulin or complement deposits.
studies
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 end-
stage 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 clinical settings.
a pathologic proteinaceous substance, deposited between cells in various organs and tissues with a wide variety of Tipically involves: – Kidneys, spleen, liver, myocardium, adrenals, thyroid, pituitary and tongue.
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 – A b 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.
S T A G E E A R L Y
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
GLOMERULUS
Extravasation due to capillary damage Fibrin Production stimulated by factors liberated by Monocytes 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
IDIOPATHIC RPGN
The implication of a cellular crescent is that the glomerulus has sustained
acute intense injury
.
Rapidly Progressive Glomerulonephritis
Pathogenesis of symptoms
Glomerular tufts adhere to Bowman’s capsule
OLIGURIA
Cicatrization of capillaries POST-GLOMERULAR ISCHEMIA
Renal Failure 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 non collagen 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, hemosiderin filled 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 crescents.
(wire loop) , and extracapillary proliferation in the form of Fibrinoid necrosis, leukocyte infiltration, wire loop 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 ¡
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MMI