Thrombotic microangiopathyIntroduction & Definitions

Ian Roberts Oxford, UK

Definition of TMA

Nephrologists:

A syndrome of thrombocytopenia and microangiopathic haemolytic anaemia (fragmented RBCs + raised LDH)

Pathologists:

The morphology of acute microvascular injury.

Alternative terms: Acute obliterative microangiopathy Malignant vascular injury

Target of injury: endothelium of interlobular arteries, arterioles, glomerular capillaries.

Inflammation is absent (not vasculitis)

TMA – factors influencing the value of the

renal biopsy report

Things to consider:

Lesion definitions & illustrations

Which lesions require definitions?

Minimum diagnostic criteria

Which histological stains to use, LM/EM

Differential diagnosis

Lesion quantification

Consistent and reproducible interpretation and quantification of lesions

is an essential prerequisite for any clinicopathological study correlating

histology with pathogenesis of TMA, prognosis and response to

therapy.

Words don’t mean the same things to all pathologists

TMA working group definitions

Working Groups

European:GermanyUK

North American:Cure-GN

International:BanffRenal Pathology Society

Potential for considerable confusion!

Läsion Vorschlag Definition

Wandhaftende Thromben in den Kapillaren

Fibrin/Thromobozyten-Aggregate in 1 oder mehr Kapillarlichtungen ohne Abstand zur Kapillarwand, mindestens die Hälfte der Fläche der Kapillarlichtung einnehmend (ohne erkennbare andere Ursache wie Cholesterin- oder Knochenmarksemboli, Fadenbestandteile usw.)

Endothelzellschwellung/-aktivierung/Endotheliose

Zunahme des Zellvolumens (Schwellung) und Vergrößerung der Zellkernes auf das mindestens 2-fache der Norm

MesangiolysenKomplette oder inkomplette Auflösung der mesangialen Matrix mit/ohne aneurysmatische Aufweitung der Kapillarlichtungen

Erythrozyten oder Erythrozytenfragmente in den Kapillarwänden bzw. im Mesangium

Mindestens 2 Erythrozyten oder Fragmente von Erythrozyten außerhalb der Kapillarlichtungen: im verbreiterten subendothelialen Raum oder im aufgelockerten Mesangium

Doppelkonturen oder MehrschichtigkeitDoppelkonturen oder Mehrschichtigkeit der peripheren Basalmembranen in mindestens 2 Kapillaren

ältere Mesangiolysefokale und segmentale lobuläre Vernarbung bzw. Sklerose ohne Hinweis auf das Vorliegen einer diabetischen Glomerulosklerose, einer LCDD oder einer Glomerulonephritis

Subendotheliale Verbreiterung/ÖdemLichtmikroskopisch erkennbarer Abstand zwischen Basalmembran und Endothelzellen in mindestens 2 Kapillaren

Glomerulärer KollapsRetrahiertes Schlingenkonvolut mit Erweiterung des Kapselraumes und geschlängelt verlaufenden bzw. gefältelten peripheren Basalmembranen

Blutleere Glomeruli keine Erythrozyten in den Kapillarlichtungen

SolidifizierungGlomeruläre Verödung mit komplettem Verlust der Endothelzellen und der Kapillarlichtungen bei zumindest teilweise noch offenem Kapselraum

Erythrozytenstase im Glomerulus bzw. Kongestion

alle Kapillaren mindestens eines Glomerulus jeweils komplett ausgefüllt mit Erythrozyten

Vermehrt Granulozyten in den glomerulären Kapillarlichtungen

Mehr als 2 Granulozyten pro Glomerulus in den Kapillarlichtungen

TMA working group definitions

Glomerular TMA definitions

Endothelial swelling (endotheliosis): Swollen endothelial cells producing occlusion or near occlusion of the capillary lumen.

Minimum diagnostic criteria: Conspicuous endothelial cytoplasm, >2x nuclear volume and occupying >50% of the space inside the GBM.

Minimum number of capillaries: 1 or >1?

Glomerular TMA definitions

Endothelial detachment: Endothelial cells within the capillary lumen, not attached to the basement membrane.

Does this require EM?

Is a CD31-PAS of value?

Glomerular TMA definitions

Glomerular thrombosis: occlusion of glomerular capillaries by fibrin or platelet rich thrombi. Differential diagnosis: Thrombosis secondary to DIC; pseudothrombi, comprising immunoglobulins.

H&E is sufficient, MSB for fibrin not necessary

Does IH for platelet markers such as CD61 have a role?

Glomerular TMA definitions

Mesangiolysis: Dissolution of the mesangial matrix, identified by reduced staining with matrix stains and swelling of the mesangial region.

What is the minimum requirement?

What is the significance of mesangiolysis without swelling?

Glomerular TMA definitions

Capillary aneurysm: Dilatation or unfolding of the glomerular capillaries secondary to mesangiolysis with loss of mesangial anchor points on the GBM. This should be distinguished from capillary dilatation secondary to passive congestion that shows global involvement of the glomerulus.

Glomerular TMA definitions

Subendothelial insudates: Expansion of subendothelial space (between the endothelium and the GBM) by protein and cell debris. These are distinct from nodular hyalinotic insudative lesions seen in diabetes, and have a flocculent appearance at EM.

Is insudation in one capillary sufficient and is the number of capillaries affected of significance?

Glomerular TMA definitions

Subendothelial insudates: Expansion of subendothelial space (between the endothelium and the GBM) by protein and cellular debris. These are distinct from nodular insudative lesions seen in diabetes, and have a flocculent appearance at EM.

On EM, how far does the endothelium have to be from the GBM?

Glomerular TMA definitions

Glomerular basement membrane duplication: Double contours seen at LM and new subendothelial basement membrane seen at EM. Distinguished from MPGN by absence of electron dense deposits.

Is the extent of GBM duplication of significance?

Glomerular TMA definitions

Glomerular basement membrane duplication: Double contours seen at LM and new subendothelial basement membrane seen at EM. Distinguished from MPGN by absence of electron dense deposits.

Is the extent of GBM duplication of significance?

Glomerular TMA definitions

Glomerular ischaemia: Collapsed, bloodless glomerular capillaries with a crenated basement membrane evident on silver stain, secondary to occlusion of arteries/afferent arterioles.

Glomerular TMA definitions

Glomerular congestion: Glomeruli showing global capillary engorgement by red blood cells, reflecting occlusion of the efferent arteriole (“Paralysed” glomeruli).

Arterial & Arteriolar TMA definitions

Thrombosis: Intraluminal thrombus that may be fibrin or platelet rich.

Arterial & Arteriolar TMA definitions

Intramural fibrin: Leakage of fibrin into the walls of vessels as a result of endothelial injury.

Arterial & Arteriolar TMA definitions

Intramural red blood cells: Leakage of red blood cells or RBC fragments into the walls of vessels as a result of endothelial injury.

Myxoid intimal swelling: Subendothelial intimal swelling by fluid with few cells and a variable component of myxoid haematoxyphilic matrix.

Subcategorised: intima more or less than thickness of underlying media.

Arterial & Arteriolar TMA definitions

Cellular intimal thickening: Intimal thickening as a result of cellular proliferation.

Subcategorised: intima more or less than thickness of underlying media.

Arterial & Arteriolar TMA definitions

Arterial & Arteriolar TMA definitions

Fibrous intimal thickening: Intimal thickening as a result of an increase in collagenous matrix. This is distinct from fibroelastosis. An EVG stain is recommended for the evaluation of chronic arterial lesions.

Subcategorised: intima more or less than thickness of underlying media.

Role of the renal biopsy

Role of the renal biopsy

Role of the renal biopsy in TMA

1. Diagnosis of TMA as the cause of the renal diseaseeg. in acute kidney injury: TMA vs RPGN

in a patient with lupus: TMA vs lupus glomerulonephritis

2. Diagnosis of an underlying renal diseaseeg. Underlying GN in TMA due to accelerated hypertension

3. PrognosticationRenal prognosis correlates with % glomeruli affected, severity of acute arterial lesions & ischaemic injury, chronic lesions – arterial fibrosis, tubular atrophy.

4. Provides clues to the aetiology of the TMANo lesion is specific for a single cause but the pattern of involvement varies slightly according to underlying condition.

5. Guiding therapyeg. Anti-complement therapy. Role of IH for complement components?