Thrombotic microangiopathy Introduction & Definitions. Ian Roberts Oxford, UK

Transkript

1 Thrombotic microangiopathy Introduction & Definitions Ian Roberts Oxford, UK

2 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)

3

4 TMA factors influencing the value of the renal biopsy report 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. Things to consider: Lesion definitions & illustrations Which lesions require definitions? Minimum diagnostic criteria Which histological stains to use, LM/EM Differential diagnosis Lesion quantification Words don t mean the same things to all pathologists

5 TMA working group definitions Working Groups European: Germany UK North American: Cure-GN Potential for considerable confusion! International: Banff Renal Pathology Society

6 TMA working group definitions Läsion Vorschlag Definition Wandhaftende Thromben in den Kapillaren Endothelzellschwellung/- aktivierung/endotheliose Mesangiolysen Erythrozyten oder Erythrozytenfragmente in den Kapillarwänden bzw. im Mesangium Doppelkonturen oder Mehrschichtigkeit ältere Mesangiolyse Subendotheliale Verbreiterung/Ödem Glomerulärer Kollaps Blutleere Glomeruli Solidifizierung Erythrozytenstase im Glomerulus bzw. Kongestion Vermehrt Granulozyten in den glomerulären Kapillarlichtungen 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.) Zunahme des Zellvolumens (Schwellung) und Vergrößerung der Zellkernes auf das mindestens 2-fache der Norm Komplette oder inkomplette Auflösung der mesangialen Matrix mit/ohne aneurysmatische Aufweitung der Kapillarlichtungen Mindestens 2 Erythrozyten oder Fragmente von Erythrozyten außerhalb der Kapillarlichtungen: im verbreiterten subendothelialen Raum oder im aufgelockerten Mesangium Doppelkonturen oder Mehrschichtigkeit der peripheren Basalmembranen in mindestens 2 Kapillaren fokale und segmentale lobuläre Vernarbung bzw. Sklerose ohne Hinweis auf das Vorliegen einer diabetischen Glomerulosklerose, einer LCDD oder einer Glomerulonephritis Lichtmikroskopisch erkennbarer Abstand zwischen Basalmembran und Endothelzellen in mindestens 2 Kapillaren Retrahiertes Schlingenkonvolut mit Erweiterung des Kapselraumes und geschlängelt verlaufenden bzw. gefältelten peripheren Basalmembranen keine Erythrozyten in den Kapillarlichtungen Glomeruläre Verödung mit komplettem Verlust der Endothelzellen und der Kapillarlichtungen bei zumindest teilweise noch offenem Kapselraum alle Kapillaren mindestens eines Glomerulus jeweils komplett ausgefüllt mit Erythrozyten Mehr als 2 Granulozyten pro Glomerulus in den Kapillarlichtungen

7 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?

8 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?

9 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?

10 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?

11 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.

12 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?

13 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?

14 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?

15 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?

16 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.

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

18 Arterial & Arteriolar TMA definitions Thrombosis: Intraluminal thrombus that may be fibrin or platelet rich.

19 Arterial & Arteriolar TMA definitions Intramural fibrin: Leakage of fibrin into the walls of vessels as a result of endothelial injury.

20 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.

21 Arterial & Arteriolar TMA definitions 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.

22 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.

23 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.

24 Role of the renal biopsy

25 Role of the renal biopsy

26 Role of the renal biopsy in TMA 1. Diagnosis of TMA as the cause of the renal disease eg. in acute kidney injury: TMA vs RPGN in a patient with lupus: TMA vs lupus glomerulonephritis 2. Diagnosis of an underlying renal disease eg. Underlying GN in TMA due to accelerated hypertension 3. Prognostication Renal 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 TMA No lesion is specific for a single cause but the pattern of involvement varies slightly according to underlying condition. 5. Guiding therapy eg. Anti-complement therapy. Role of IH for complement components?