renal ultrastructural pathology lecture 1 a - c
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Basic Renal EM workshop Southampton September 30 th 2011. Renal Ultrastructural Pathology Lecture 1 A - C. Bart E Wagner BSc CSc FIBMS Dip Ult Path Chief Biomedical Scientist Electron Microscopy Section Histopathology Department Northern General Hospital Sheffield - PowerPoint PPT PresentationTRANSCRIPT
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Renal Ultrastructural PathologyRenal Ultrastructural PathologyLecture 1 A - CLecture 1 A - C
Bart E Wagner Bart E Wagner BSc CSc FIBMS Dip Ult PathBSc CSc FIBMS Dip Ult Path
Chief Biomedical ScientistChief Biomedical ScientistElectron Microscopy SectionElectron Microscopy SectionHistopathology DepartmentHistopathology DepartmentNorthern General HospitalNorthern General Hospital
SheffieldSheffieldSouth YorkshireSouth Yorkshire
UKUKS5 7AUS5 7AU
[email protected]+44(0)114-27 14154Tel+44(0)114-27 14154
Basic Renal EM workshop
Southampton
September 30th 2011
Histopathology DepartmentNorthern General Hospital
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Renal Ultrastructural PathologyRenal Ultrastructural PathologyLecture 1 - TopicsLecture 1 - Topics
1.1. Alport’s nephritisAlport’s nephritis
2.2. AmyloidAmyloid
3.3. Capsular adhesionCapsular adhesion
4.4. Congenital nephrotic syndromeCongenital nephrotic syndrome
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Alport’s nephritisAlport’s nephritis
1
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Alport’s nephritisAlport’s nephritis
Collagen IV gene defectCollagen IV gene defect
Affecting all glomerular basement membranesAffecting all glomerular basement membranes
X-linked is most common form (80%) ie results in males X-linked is most common form (80%) ie results in males being more severely affected, and affected earlier in life. being more severely affected, and affected earlier in life. (Col IV alpha 5 & 6)(Col IV alpha 5 & 6)
Recessively inherited form (Col IV alpha 3 & 4 on Recessively inherited form (Col IV alpha 3 & 4 on chromosome 2)chromosome 2)
Part of syndrome – frequently also affects hearing, Part of syndrome – frequently also affects hearing, occasionally ocularoccasionally ocular
Due to GBM defect, persistent microscopic haematuria Due to GBM defect, persistent microscopic haematuria present present
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Alport’s Alport’s 25 year old male25 year old male
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Tubular thyroidisation - Segmental glomerular sclerosis - Interstitial foam cells
End stage Alport’s nephritis
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Interstitial foam cells (fibroblasts filled with saturated lipid droplets)
Higher magnification of above
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Higher magnification of first Alport’s image
Segmental sclerosis, extensive foot process effacement, all capillary loops affected
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Alport’s syndrome
Irregularly thickened GBM GBM in multiple layers
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Alport’s syndrome
Focally thin GBM
GBM in multiple layers
Higher magnification of previous slide
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Alport’s Alport’s 50 year old female50 year old female
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Foot process effacement, lamination of GBM
Higher magnification of previous slide
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Lamination/reticulation/reduplication of GBM, foot process effacement
Higher magnification of previous slide
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Alport’s nephritisAlport’s nephritis
How to diagnose thin basement How to diagnose thin basement membrane diseasemembrane disease
AllAll the GBM’s are thin the GBM’s are thin
All other diagnoses are excluded - especially IgA diseaseAll other diagnoses are excluded - especially IgA disease
GeneticsGeneticsEither, early X-linked Alport’sEither, early X-linked Alport’s
Or, heterozygous autosomal Alport’sOr, heterozygous autosomal Alport’s
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Alport’s Alport’s 14 year old male14 year old male
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14 year old boy with thin GBM, haematuria, but not nephrotic
All GBM’s are thin, no deposits
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Thin GBM approx 190nm instead of normal 300nm, with small areas of minor lamination
Alport’s – 14 year old boy
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Renal AmyloidRenal Amyloid
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Renal AmyloidRenal Amyloid
Electron Microscopy is gold standard test for amyloidElectron Microscopy is gold standard test for amyloid
BecauseBecause
10 – 20 % of cases of amyloid, irrespective of type, do not stain with 10 – 20 % of cases of amyloid, irrespective of type, do not stain with Congo or Sirius RedCongo or Sirius Red
Amount of amyloid can be below amount detected by light Amount of amyloid can be below amount detected by light microscopy, but still be sufficient to cause severe proteinuriamicroscopy, but still be sufficient to cause severe proteinuria
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Almost end stage glomerulus
Amyloid present diffusely in glomerulus
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Predominantly mesangial amyloid
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Extensive mesangial deposition of amyloid compromising capillary lumens
Note: variable density of amyloid deposition
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Amyloid fibrils
Amyloid fibrils are 7 – 10nm diameter, straight and extracellular
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Interstitial foam cells
Amyloid in patient with Crohn’s disease
Mild disease, but with evidence of chronic proteinuria
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‘Spicular’ on MST stain, amyloid Subepithelial amyloid
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Subepithelial spicular amyloid
Podocyte nucleus Condensed filamentous actin Stage 1
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Subepithelial amyloid, at later stages to previous slides
Stage 2 Stage 3
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Higher magnification of previous slide at stage 2
Deposited amyloid fibrils unable to bind to laminin
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Higher magnification of subepithelial amyloid fibrils
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Subepithelial/mesangial amyloid resulting in podocyte loss
Urine space Stage 3 – visible on tol blue
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Perivascular amyloid Vascular smooth muscle cells
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Systemic amyloid can deposit in other Systemic amyloid can deposit in other locations less commonly, such as..locations less commonly, such as..
SubendotheliallySubendothelially
Renal interstitiumRenal interstitium
On tubular basement membraneOn tubular basement membrane
In tubular lumenIn tubular lumen
Localised amyloid (amyloidoma) Localised amyloid (amyloidoma) Closely associated with an aggregate of plasma cells in interstitiumClosely associated with an aggregate of plasma cells in interstitium
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Subendothelial amyloid
Patient with Porphyria
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Amyloid in interstitium Different case to previous slide
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Renal interstitial amyloid Higher magnification of previous slide
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Amyloid in renal interstitium
Fibrils of fibrous collagen Amyloid fibrils
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Amyloid on tubular basement membrane Different case to previous slide
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Laminated intratubular lumen, sirius red positive, cast in patient with myeloma
Different case to previous slide
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Nodular/localised amyloid associated with aggregate of plasma cells in renal interstitium
Different case to previous slide
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Capsular adhesionCapsular adhesion
3
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Capsular adhesionCapsular adhesion
MechanismMechanismPodocyte loss associated with severe proteinuriaPodocyte loss associated with severe proteinuria
If it occurs adjacent to Bowman’s capsuleIf it occurs adjacent to Bowman’s capsule
Apex of parietal epithelial cell adheres to naked GBMApex of parietal epithelial cell adheres to naked GBM
Significance Significance
Indicator of podocyte damage not caused by lack of Indicator of podocyte damage not caused by lack of adherence.adherence.
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Capsular adhesion – first stage
Incipient epithelial break – early podocyte degeneration
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Capsular adhesion – parietal epithelial cell Bowman’s capsule
Area of previously denuded GBM
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Congenital nephrotic syndromeCongenital nephrotic syndrome
4
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Congenital nephrotic syndromeCongenital nephrotic syndrome
Nephrin gene defectNephrin gene defect
Autosomal recessively inheritedAutosomal recessively inherited
No slit diaphragm seen between podocyte foot No slit diaphragm seen between podocyte foot processes in most affected individualsprocesses in most affected individuals
Survival is rare over the age of 4 – often succumb to Survival is rare over the age of 4 – often succumb to Gram negative septicaemia due to hypocomplentaemiaGram negative septicaemia due to hypocomplentaemia
Transplant only treatment option currentlyTransplant only treatment option currently
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Congenital nephrotic syndrome
10 month old child – initially thought to have heart failure
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100% foot process effacement
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100% foot process effacement GBM appears thin due to age of patient – 10 months
Congenital nephrotic syndrome
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Time for a quick break?Time for a quick break?
‘The mind cannot absorb what the backside cannot endure’‘The mind cannot absorb what the backside cannot endure’
Prince Philip ,The Duke of Edinburgh.