renal allograft path July2011

Classification of Renal Allograft Rejection – Banff Criteria: 

Classification of Renal Allograft Rejection – Banff Criteria Dr. S. Rajendiran, MD, Dip.R.C.Path, AB (AP&CP), AB (Cyto) Professor of Pathology Sri Ramachandra Medical College & Research Institute Chennai, India

Game Plan: 

Game Plan Introduction Diagnostic categories Specimen adequacy Banff criteria for rejection Take home message

Introduction Renal Allograft Rejection – Banff Criteria: 

Introduction Renal Allograft Rejection – Banff Criteria Standardization of renal allograft biopsy report To guide therapy To establish objective endpoint for clinical trails To reduce the inter & intra observer variability in the interpretation

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The Banff working classification of renal allograft pathology: International schema originated in Banff, Canada on Aug 2-4, 1991 Banff, Canada

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Charming resort town in Canadian Rockies Playground for outdoor enthusiasts, mountaineers and nature-lovers From 1991, meetings every 2 yrs to refine the criteria of allograft pathology Banff ’97 classification is widely used, updated in 2001, 2003, 2005, 2007, 2009 Banff, Canada

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1991, 93, 95, 97, 99, 2001,03,05,07,09, 11…..... 11 conferences so for…. 1. 1991 – First conference 3. 1995 - Chronic Allograft Damage Index (CADI) scoring 4. 1997 – Integration with CCTT classification (Collaborative Clinical Trails in transplantation) 2. 1993 – First paper on Banff working classification 5. 1999 – Second paper “ The Banff 97 working classification of renal allograft pathology Banff Conferences

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1991, 93, 95, 97, 99, 2001,03,05,07,09, 11 11 conferences so for…. 6. 2001 – Classification of antibody mediated rejection 8. 2005 – Edmonton, Canada 1. Elimination of CAN 2. Recognition of chronic AB mediated rejection 7. 2003 – Aberdeen,Scotland Updates on schemas of allograft rejection 1. Chronic allograft nephropathy (CAN) 2. Genomics of rejection 3. Antibody mediate rejection/c4d Banff Conferences

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1991, 93, 95, 97, 99, 2001,03,05,07,09, 11….11 conferences so for.. Banff Conferences 9. 2007 – La Coruna, Spain – Major update in Banff 2007 Classification 1. Inclusion of grading of peritubular capillaritis 2. C4d scoring 3. Interpretation of C4d without morphological evidence of active rejection 4. Application of Banff criteria to zero time and protocol biopsies 5. New scoring for total interstitial inflammation (ti-score) 6. To include molecular parameters in the Banff system in future 10. 2009 – Conceptualize alloantibody responses and related phenotypes 1. Genomics/proteomics approaches to rejection diagnosis 2. Non-invasive surrogate markers of rejections 3. Role of endothelial cell in rejection 4. Phenotyping of late kidney transplant deterioration 11. 2011 – Paris, France – Report to follow

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Evolution of renal rejection terminologies Clinical Pathogenetic Morphological Acute Chronic Acute (grades I,II,III - t,i,v,g) Chronic (grades I,II,III -ct,ci,cv,ah,cg, mm) Interstitial fibrosis and tubular atrophy (grades I,II,III) Antibody mediated (B cell) Cell mediated (T cell) Normal Borderline Others Acute Chronic active Chronic sclerosing Allograft Nephropathy (CAN-grade I,II,III)

Banff 2007 Diagnostic categories Update: 

Banff 2007 Diagnostic categories Update Normal Antibody mediated changes (coincide with 3,4,5,6) Borderline changes (coincide with 2,5,6) T cell – mediated rejection (coincide with 2,5,6) Interstitial fibrosis and tubular atrophy (coincide with 2,3,4,6) Other (coincide with 2,3,4,5)

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Serological Circulating Donor Specific Antibody (DSA) Morphological No morphological changes With morphological changes Acute Chronic active IF/IHC C4d positive Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other All 3 positive – Diagnostic 1 or 2 positive - Suggestive

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Morphological - No morphological changes With morphological changes Acute (AAMR) ATN like minimal inflammation Capillary/ glomerular inflammation/ thrombosis Arterial changes (v3) Chronic active (CAAMR) Glomerular double contours Peritubular capillary BM multilayering Interstitial fibrosis/ tubular atrophy Fibrous intimal thickening in arteries Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other All 3 positive – Diagnostic 1 or 2 positive - Suggestive Serological Morphological IF/IHC

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Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other Suspicious for T cell mediated rejection No vasculitis Tubulitis with minor interstitial inflammation Moderate interstitial inflammation with minor tubulitis

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Acute T cell mediated rejection (ATMR) Tubulitis Intes. Inflam. Vasculitis IA. Moderate Significant Absent IB Severe Significant Absent IIA Any degree Mild/moderate IIB Any degree Severe III Any degree Extensive Chronic active T cell mediated rejection (CATMR) Chronic allograft arteriopathy Arterial intimal fibrosis with mononuclear cell infiltration Formation of neo intima Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other

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Grade I Mild interstitial fibrosis and tubular atrophy II Moderate interstitial fibrosis and tubular atrophy III Severe interstitial fibrosis and tubular atrophy (May include non specific vascular and glomerular sclerosis but graded by tubulointerstitial features) Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other

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Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other Etiology Morphology (in addition to IF and TA) Chronic hypertension 1. Arterial fibrointimal thickening with reduplication of elastica – small arteries 2. Arteriolar hyaline changes Diabetes Nodular glomerular sclerosis Hyaline cap Capsular drop Arteriolar sclerohyalinosis CNI toxicity Isometric vacuolization of tubular cells Arteriolar hyalinosis Strip fibrosis Chronic obstruction Marked tubular dilatation Large Tom Horsfall protein casts (extravasation in to interstitium /lymphatics) Bacterial pyelonephritis Intratubular and peritubular neutrophils Lymphoid follicles in the interstitium Viral pyelonephritis CMV (H&E, IHC, EM) BK virus

Others: 

Others Preservation injury Drug Toxicity Infection PTLD Non-lymphoid neoplasms

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Specimen Adequacy (a necessary prerequisite for numeric coding) Unsatisfactory Less than 7 glomeruli & no arteries Marginal 7 glomeruli with one artery Adequate 10 or more glomeruli with at least two arteries Minimum Sampling 7 slides 3 H&E, 3 PAS or silver stains, and 1 trichrome, section thickness 3-4 microns. The Banff 97 working classification of renal allograft pathology

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ATN – Like

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Quantitative criteria for cortical Peritubular capillaritis (ptc)

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ptc1. v1

Antibody Mediated Rejection: 

Antibody Mediated Rejection Interstitial hemorrhage ptc3

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ptc 3- AAMR

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Hypercellularity with neutrophils

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Fibrinoid necrosis of glomerulus

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Fraser Lendrum

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v3 – AAMR

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v3 – AAMR

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Quantitative criteria for cortical C4d scoring in Peritubular capillaries

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C4d - AAMR

Antibody Mediated Rejection: 

Antibody Mediated Rejection Diffuse (>50%) C4d staining on IF Diagnosis : Banff acute antibody mediated rejection

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C4d - IHC

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Double contours – CAAMR

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Multilayering of PTC BM- CAAMR

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IF/TA Fibrous intimal thickening C4d

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Intestitial plasma cells

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Morphological - No morphological changes With morphological changes Acute ATN like - minimal inflammation Capillary/ glomerular inflammation/ thrombosis Arterial changes (v3) Chronic active Glomerular double contours Peritubular capillary BM multilayering Interstitial fibrosis, plasma cells/ tubular atrophy Fibrous intimal thickening in arteries Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other All 3 positive – Diagnostic 1 or 2 positive - Suggestive Serological Morphological IF/IHC

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Acute T cell mediated rejection (ATMR) Tubulitis Intes. Inflam. Vasculitis IA. Moderate Significant Absent IB Severe Significant Absent IIA Any degree Mild/moderate IIB Any degree Severe III Any degree Extensive Chronic active T cell mediated rejection (CATMR) Chronic allograft arteriopathy Arterial intimal fibrosis with mononuclear cell infiltration Formation of neo intima Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other

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Acute Changes Tubulitis: t0 t1 t2 t3 Intimal arteritis: v0 v1 v2 v3 Interstitial inflammation: i0 i1 i2 i3 Glomerulitis: g0 g1 g2 g3 Chronic changes Tubular atrophy: ct0 ct1 ct2 ct3 Interstitial fibrosis: ci0 ci1 ci2 ci3 Allograft glomerulopathy: cg0 cg1 cg2 cg3 Mesangial matrix increase: mm0 mm1 mm2 mm3 Fibrous intimal thickening: cv0 cv1 cv2 cv3 Drug toxicity Arteriolar hyaline thickening: ah0 ah1 ah2 ah3 Semiquantitative Scoring of Changes

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Quantitative Criteria for Tubulitis ("t") Score t0 No mononuclear cells in tubules t1 Foci with 1 to 4 cells/tubular cross section or 10 tubular cells t2 Foci with 5 to 10 cells/tubular cross section t3 Foci with >10 cells/tubular cross section, or the presence of at least two areas of tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 tubulitis elsewhere in the biopsy.

t0: No mononuclear cells in tubules : 

t0 : No mononuclear cells in tubules

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t1: Foci with 1 to 4 cells/tubular cross section or 10 tubular cells

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t2: Foci with 5 to 10 cells/tubular cross section

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t3 : Foci with >10 cells/tubular cross section or t2 tubulitis + i2/i3 + at least two areas of tubular basement membrane destruction

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Quantitative Criteria for Mononuclear Cell Interstitial Inflammation ("i") i0 No or trivial interstitial inflammation (<10% of unscarred parenchyma) i1 10 to 25% of parenchyma inflamed cells i2 26 to 50% of parenchyma inflamed i3 >50% of parenchyma inflamed Indicate presence of remarkable numbers (>10% of total cells) of eosinophils, polys, or plasma cells (specify which) with an asterisk on i

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i0: No or trivial interstitial inflammation (<10% of unscarred parenchyma)

i1: 10 to 25% of parenchyma inflamed cells : 

i1 : 10 to 25% of parenchyma inflamed cells

i2: 26 to 50% of parenchyma inflamed : 

i2 : 26 to 50% of parenchyma inflamed

i3:>50% of parenchyma inflamed : 

i3 : >50% of parenchyma inflamed

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Quantitative Criteria for Intimal Arteritis ("v") v0 No arteritis v1 Mild-to-moderate intimal arteritis in at least one arterial cross section v2 Severe intimal arteritis with at least 25% luminal area lost in at least one arterial cross section v3 Arterial fibrinoid change and/or transmural arteritis with medial smooth muscle necrosis with lymphocytic inflammation Note number of arteries present and number affected. Indicate infarction and/or interstitial hemorrhage by an asterisk (with any level v score)

v0: No arteritis : 

v0 : No arteritis

v1:Mild-to-moderate intimal arteritis in at least one arterial cross section : 

v1 : Mild-to-moderate intimal arteritis in at least one arterial cross section

v2: Severe intimal arteritis with at least 25% luminal area lost in at least one arterial cross section : 

v2 : Severe intimal arteritis with at least 25% luminal area lost in at least one arterial cross section

v3: Arterial fibrinoid change and/or transmural arteritis with medial smooth muscle necrosis with lymphocytic inflammation : 

v3 : Arterial fibrinoid change and/or transmural arteritis with medial smooth muscle necrosis with lymphocytic inflammation

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Quantitative Criteria for the Early Type of Allograft Glomerulitis ("g") (mononuclear infiltrate or endothelial swelling) g0 No glomerulitis g1 Glomerulitis in <25% of glomeruli g2 Segmental or global glomerulitis in about 25 to 75% of glomeruli g3 Glomerulitis (mostly global) in >75% glomeruli Neutrophil infiltrate not included – may represent Ab mediated rejection or early thrombotic microangiopathy

g0: No glomerulitis : 

g0: No glomerulitis

g1:Glomerulitis in <25% of glomeruli: 

g1 :Glomerulitis in <25% of glomeruli

g2: Segmental or global glomerulitis in about 25 to 75% of glomeruli : 

g2 : Segmental or global glomerulitis in about 25 to 75% of glomeruli

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Normal Antibody mediated changes Borderline changes T cell – mediated rejection Interstitial fibrosis and tubular atrophy Other Suspicious for T cell mediated rejection No vasculitis (V0) Tubulitis (t1-3) with minor interstitial inflammation (i1) Moderate interstitial inflammation (i2-3) with minor tubulitis (t1)

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Acute T cell mediated rejection t1, i1,vo, go Diagnosis : Borderline changes suspicious for TCMR

Acute Rejection: 

Acute Rejection 5 to 10 lymphocytes/ tube: t2 30% interstitial inflammation: i2 go, vo Diagnosis: TCMR – I B

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Quantitative Criteria for Allograft Glomerulopathy ("cg") cg0 No glomerulopathy, double contours in <10% of peripheral capillary loops in most severely affected glomerulus cg1 Double contours affecting up to 25% of peripheral capillary loops in the most affected of nonsclerotic glomeruli cg2 Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli cg3 Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli Note number of glomeruli and percentage sclerotic

cg0: No glomerulopathy, double contours in <10% of peripheral capillary loops in most severely affected glomerulus : 

cg0 : No glomerulopathy, double contours in <10% of peripheral capillary loops in most severely affected glomerulus

cg1:Double contours affecting up to 25% of peripheral capillary loops in the most affected of nonsclerotic glomeruli : 

cg1 : Double contours affecting up to 25% of peripheral capillary loops in the most affected of nonsclerotic glomeruli

cg2: Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli : 

cg2 : Double contours affecting 26 to 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli

cg3:Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli : 

cg3 : Double contours affecting more than 50% of peripheral capillary loops in the most affected of nonsclerotic glomeruli

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Quantitative Criteria for Interstitial Fibrosis ("ci") ci0 Interstitial fibrosis tissue in up to 5% of cortical area ci1 Mild- Interstitial fibrosis tissue in 6 to 25% of cortical area ci2 Moderate- interstitial fibrosis of 26 to 50% of cortical area ci3 Severe interstitial fibrosis of >50% of cortical area

ci0:Interstitial fibrosis tissue in up to 5% of cortical area : 

ci0 : Interstitial fibrosis tissue in up to 5% of cortical area

ci1:Mild- Interstitial fibrosis tissue in 6 to 25% of cortical area : 

ci1 : Mild- Interstitial fibrosis tissue in 6 to 25% of cortical area

ci2: Moderate- interstitial fibrosis of 26 to 50% of cortical area : 

ci2 : Moderate- interstitial fibrosis of 26 to 50% of cortical area

ci3:Severe interstitial fibrosis of >50% of cortical area : 

ci3 : Severe interstitial fibrosis of >50% of cortical area

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Quantitative Criteria for Tubular Atrophy ("ct") ct0 No tubular atrophy ct1 Tubular atrophy in up to 25% of the area of cortical tubules ct2 Tubular atrophy involving 26 to 50% of the area of cortical tubules ct3 Tubular atrophy of >50% of the area of cortical tubules

ct0: No tubular atrophy : 

ct0 : No tubular atrophy

ct1: Tubular atrophy in up to 25% of the area of cortical tubules : 

ct1: Tubular atrophy in up to 25% of the area of cortical tubules

ct2: Tubular atrophy involving 26 to 50% of the area of cortical tubules : 

ct2: Tubular atrophy involving 26 to 50% of the area of cortical tubules

ct3: Tubular atrophy of >50% of the area of cortical tubules : 

ct3 : Tubular atrophy of >50% of the area of cortical tubules

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Quantitative Criteria for Fibrous Intimal Thickening ("cv") cv0 No chronic vascular changes cv1 Vascular narrowing of up to 25% luminal area by fibrointimal thickening of arteries ± breach of internal elastic lamina or presence of foam cells or occasional mononuclear cells * cv2 Increased severity of changes described above with 26 to 50% narrowing of vascular luminal area * cv3 Severe vascular changes with >50% narrowing of vascular luminal area * * in most severely affected vessel. Note if lesions characteristic of chronic rejection (elastica breaks, inflammatory cells in fibrosis, formation of neointima) are seen

cv0: No chronic vascular changes : 

cv0 : No chronic vascular changes

cv1: Vascular narrowing of up to 25% luminal area by fibrointimal thickening of arteries ± breach of internal elastic lamina or presence of foam cells or occasional mononuclear cells: 

cv1 : Vascular narrowing of up to 25% luminal area by fibrointimal thickening of arteries ± breach of internal elastic lamina or presence of foam cells or occasional mononuclear cells

cv2: Increased severity of changes described above with 26 to 50% narrowing of vascular luminal area* : 

cv2 : Increased severity of changes described above with 26 to 50% narrowing of vascular luminal area *

cv3: Severe vascular changes with >50% narrowing of vascular luminal area: 

cv3 : Severe vascular changes with >50% narrowing of vascular luminal area

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Quantitative Criteria for Mesangial Matrix Increase ("mm")* mm0 No mesangial matrix increase mm1 Up to 25% of nonsclerotic glomeruli affected (at least moderate matrix increase) mm2 26-50% of nonsclerotic glomeruli affected (at least moderate matrix increase) mm3 >50% of nonsclerotic glomeruli affected (at least moderate matrix increase) * The threshold criterion for the moderately increased "mm" is the expanded mesangial interspace between adjacent capillaries. If the width of the interspace exceeds two mesangial cells on the average in at least two glomerular lobules the "mm" is moderately increased

mm0: No mesangial matrix increase : 

mm0 : No mesangial matrix increase

Banff mm1-3 scores have a similar appearance and are separated by the number of involved glomeruli (1-25% for mm1; 26-50% for mm2; >50% for mm3): 

Banff mm1-3 scores have a similar appearance and are separated by the number of involved glomeruli ( 1-25% for mm1; 26-50% for mm2; >50% for mm3)

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Quantitative Criteria for Arteriolar Hyaline Thickening ("ah") ah0 No PAS-positive hyaline thickening ah1 Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole ah2 Moderate-to-severe PAS-positive hyaline thickening in more than one arteriole ah3 Severe PAS-positive hyaline thickening in many arterioles Indicate arteriolitis (significance unknown) by an asterisk on ah

ah0: No PAS-positive hyaline thickening : 

ah0 : No PAS-positive hyaline thickening

ah1:Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole : 

ah1 : Mild-to-moderate PAS-positive hyaline thickening in at least one arteriole

ah2: Moderate-to-severe PAS-positive hyaline thickening in more than one arteriole : 

ah2 : Moderate-to-severe PAS-positive hyaline thickening in more than one arteriole

ah3:Severe PAS-positive hyaline thickening in many arterioles : 

ah3 :Severe PAS-positive hyaline thickening in many arterioles

Chronic active T cell mediated rejection: 

Chronic active T cell mediated rejection Chronic allograft arteriopathy Arterial intimal fiborsis with mononuclear cell infiltration in the fibrosis and formation of neo-intima

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Intimal fibrosis & Duplication of IEL

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Alternate to ah(aah)-evaluated for next2years

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Quantitative criteria Mononuclear cell interstitial inflammation (ti)

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T I V G ATN ptc 0 1 2 3 ptc BM duplication Tubulitis(t) Tub.Atr.(ct) Inflam(i) Plasma cells Intes.fib(ci) 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 Vasculitis(v) 0 1 2 3 Fib intimal thick(cv) 0 1 2 3 Glomerulitis(g) 0 1 2 3 Double Contour(cg) 0 1 2 3 Arte.hyn. thickening(ah) 0 1 2 3 Mes.mat. exp(mm) 0 1 2 3 Normal DSA/C4d Pos Neg AAMR No mor.evi. AAMR CAAMR Borderline ATMR Ia ATMR Ib ATMR IIa ATMR IIb ATMR III CATMR IF/TA I IF/TA III IF/TA II N Y N Y N Others Y

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T I V G ATN ptc 0 1 2 3 ptc BM duplication Tubulitis(t) Tub.Atr.(ct) Inflam(i) Plasma cells Intes.fib(ci) 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 Vasculitis(v) 0 1 2 3 Fib intimal thick(cv) 0 1 2 3 Glomerulitis(g) 0 1 2 3 Double Contour(cg) 0 1 2 3 Arte.hyn. thickening(ah) 0 1 2 3 Mes.mat. exp(mm) 0 1 2 3 Normal DSA/C4d Pos Neg AAMR No mor.evi. AAMR CAAMR Borderline ATMR Ia ATMR Ib ATMR IIa ATMR IIb ATMR III CATMR IF/TA I IF/TA III IF/TA II N Y N Y N Y Others

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T I V G ATN ptc 0 1 2 3 ptc BM duplication Tubulitis(t) Tub.Atr.(ct) Inflam(i) Plasma cells Intes.fib(ci) 0 1 2 3 0 1 2 3 0 1 2 3 0 1 2 3 Vasculitis(v) 0 1 2 3 Fib intimal thick(cv) 0 1 2 3 Glomerulitis(g) 0 1 2 3 Double Contour(cg) 0 1 2 3 Arte.hyn. thickening(ah) 0 1 2 3 Mes.mat. exp(mm) 0 1 2 3 Normal DSA/C4d Pos Neg AAMR No mor.evi AAMR CAAMR Borderline ATMR Ia ATMR Ib ATMR IIa ATMR IIb ATMR III CATMR IF/TA I IF/TA III N Y N Y N Y Others IF/TA II 5 4 3 1 2 6

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Thank you and Have a great day ………… ..