Peritubular Capillary Inflammatory Cell Accumulation Scoring

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Peritubular Capillary Inflammatory Cell
Accumulation Scoring

• Dr Ian W. Gibson
• Associate Professor, Pathology
• University of Manitoba

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Peritubular Capillary Inflammatory Cell
Accumulation Scoring - Objectives

• Review importance of assessment of PTC in renal
  allograft pathology
• Illustrate the PTC inflammatory cell accumulation
  (ptc) score proposed at Banff 2003 conference
• My experience with applicability usefulness of
  proposed ptc score (NB. work in progress)

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Peritubular Capillary Lesions in Renal Allograft
Biopsies

• Acute lesions
• Inflammatory cell accumulation / margination /
  dilatation (AR)
• Ig complement (C4d) deposition (AbMAR)
• Microthrombi (TMA)
• Chronic lesions
• Basement membrane multilayering (CR)
• Complement (C4d) deposition (AbMCR)
• Progressive injury loss (CAN)

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Peritubular Capillaritis in Renal Transplants
NEPHROL discussion Nov 1994

• Daniel Salomon A lesion Byron Croker and I
  found very interesting the presence of a
  peritubular capillary lymphocytic infiltrate,
  usually more prominent at the corticomedullary
  junction typically of lymphocytes but also
  sometimes PMNLs associated with rejection in
  over 50 cases biopsies for DGF within 10-14 days
  post-Tx also in otherwise classic acute TI
  rejection at later time points Should these
  lesions be studied in the context of the Banff
  schema?
• Kim Solez Like acute glomerulitis, peritubular
  capillaritis is likely to be a very heterogeneous
  lesion, sometimes due to rejection, sometimes CsA
  toxicity, sometimes due to ATN The peritubular
  accumulation of PMNLs is highly suggestive of
  AbMAR accumulation of mononuclear cells can
  have a number of different etiologies I myself
  doubt that peritubular capillaritis will turn out
  to be useful except when it involves PMNLs
• Michael Kashgarian My experience is similar
  I have found capillaritis in a number of
  instances i.e. ATN, CsA toxicity and rejection.
  It did not help to distinguish rejection from the
  other entities. We probably should note it
  without giving it any specific diagnostic
  significance

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PTC Inflammatory Lesions

• PMNL accumulation in AbMAR with antidonor HLA
  class I or II Ab (Halloran et al 1990, 1992,
  Trpkov et al 1996, Collins et al 1999, Mauiyyedi
  et al 2002) ABO incompatibility (Morozumi et al
  2001)
• PMNL accumulation correlates with C4d (Magil
  Tinckam 2003)
• Platelet accumulation PMNLs in AbMAR (Meehan et
  al 2003)

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PTC Inflammatory Lesions

• Endothelial cell necrosis mononuclear cell
  accumulation noted in some cases of AbMAR (Lajoie
  1997)
• Endothelial cell swelling, apoptosis, lysis,
  fragmentation marginating degranulated
  mononuclear cells PMNLs in AbMAR (Liptak et al,
  Banff 2003 abstract)
• Mononuclear cell accumulation dilatation
  correlates with C4d in CR, but no clear
  association with interstitial rejection (Regele
  et al 2002)

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C4d PTCs with mononuclear inflammatory cell
accumulation - The pathogenic or diagnostic
relevance of inflammatory cells accumulating in
PTC is currently not clear (Regele et al J Am
Soc Nephrol 132371-2380, 2002)
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AbMAR, g3 with TMA, severe ATN PMNLs in PTC
Mac387
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The Point of Banff

• Directing the eye / mind of the pathologist to
  relevant areas of the Bx, which for acute
  rejection are
• glomerulitis g score
• interstitial inflammation i score
• lymphocytic tubulitis t score
• intimal / transmural arteritis v score
• By the same principle, in particular for AbMAR, a
  further highly relevant area is
• peritubular capillaritis - ? ptc score

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Proposal Banff ptc score

• ptc 0 no significant cortical peritubular
  inflammatory changes
• ptc 1 cortical peritubular capillary with 3 to
  4 luminal inflammatory cells
• ptc 2 cortical peritubular capillary with 5 to
  10 luminal inflammatory cells
• ptc 3 cortical peritubular capillary with gt10
  luminal inflammatory cells

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Proposal Banff ptc score, notes

• numbers refer to highest number of all types of
  inflammatory cells (PMNLs, lymphocytes, monocyte
  / macrophage)
• indicates cells are mononuclear only
• indicate extent of lesion when not diffuse (gt50)
• indicate if PTCs are dilated
• exclude cells in PTC from i score (PAS, silver
  stains optimal)
• avoid scoring in subcapsular cortex, areas of
  necrosis / infarction areas of pyelonephritis

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ptc0, PTCs with 1-2 mononuclear cells only
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ptc1, mononuclear cells only
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ptc1, PMNLs
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7 days post-Tx, AbMAR, ptc2, PMNLs mononuclear
cells
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7 days post-Tx, AbMAR, ptc2, PMNLs mononuclear
cells
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ptc2, PMNLs mononuclear cells
ptc2, mononuclear cells PMNLs
ptc2, mononuclear cells PMNLs
ptc2, mononuclear cells only
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ptc2, mononuclear cells only
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ptc2, mononuclear cells only (n8)
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10 weeks post-Tx, AbMAR, ptc3, mononuclear cells
PMNLs
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2 days post-Tx, ptc3, PMNLs only, n14
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ptc3, mononuclear cells PMNLs
ptc3, mononuclear cells PMNLs
ptc3, mononuclear cells only (n11)
ptc3, mononuclear cells only (n12)
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Banff IB AR (g1,i2,t3,v0,ptc3)
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Banff IIA AR, i3,t3,v1,ptc3, eosinophil-rich
int. hemorrhage
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Banff IIA AR, i3,t3,v1,ptc3, eosinophil-rich,
int. hem. C4d
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ptc2 C4d
ptc2 C4d
ptc2 C4d -
ptc2 C4d -
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LCA
CD3
CD68
CD68
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(No Transcript)
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Longitudinally sectioned PTC, c/w ptc2
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Peritubular (ptc) versus interstitial (i)
infiltrates
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Peritubular (ptc) versus interstitial (i)
infiltrates
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Peritubular capillaritis (ptc2 ptc3) with
dilatation
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Venule with inflammatory cell accumulation
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Vasa recta infiltrates in medulla
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Applicability of ptc score

• The ptc score, as proposed at Banff 03, is
  applicable to adequate renal allograft Bxs
• It does require more time / dedication to the LM
  examination
• Assessment of extent of Bx involved is
  challenging, suggest limiting to diffuse (gt50)
  versus focal (lt50)
• Avoid scoring, or make allowance for,
  longitudinally sectioned PTCs
• Assessment of dilatation very subjective
• PTCs must be distinguished from venules vasa
  recta

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Diagnostic utility of ptc score

• The ptc score does not equate with specific
  diagnoses, but is helpful to include in overall
  assessment of an allograft Bx, as part of
  clinicopathological correlation
• The ptc score often appears to correlate with
  overall inflammatory activity, but in
  occasional allograft Bxs peritubular inflammation
  can be the predominant lesion
• Distinguishing ptc score with without () PMNLs
  is worthwhile, as literature does associate PMNLs
  with AbMAR, but seeing some PMNLs does not make a
  diagnosis of AbMAR
• The ptc score is helpful for comparison of
  sequential Bxs, e.g. assessing responses to
  therapy
• The ptc score, like all Banff scores, should be
  useful in assessing allograft Bxs for clinical
  trials
• Reproducibility of ptc score needs to be tested /
  proven

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ptc scoring useful for comparison of sequential
biopsies
A case of AbMAR
g1i2t1v0 ptc2
g0i0t1v0 ptc3
g0i2t1v0 ptc1
g0i2t1v0 ptc2
g0i1t1v0 ptc2
Creatinine (mmol/L)
Days Post-Transplant
Clinical data P Nickerson
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Peritubular capillaritis in early renal allograft
is associated with the development of chronic
rejection and chronic allograft nephropathyAita
et al Clin Transplant 19 (Suppl.14)20-26 2005

• Evaluated PTCitis (using Banff 03 ptc score) in
  early allografts with ACR (n15), AbMAR (n8),
  ptc 1/2 only (n16) no AR/ptc0 (n14) in
  subsequent later Bxs
• ptc score highest in AbMAR group (in early
  allografts, ptc scores of 2 or 3 are highly
  suggestive of acute/active rejection by humoral
  immunity)
• In some cases, PTCitis persisted, ptc score
  gradually increased during follow-up
• gt30 of cases with ptc1/2 only in early Bx
  progressed to CR, suggesting need to monitor for
  ptc1/2 in early allografts follow-up closely to
  prevent later development of CR
• Data proved the applicability of the Banff 03 ptc
  score regarded as reliable adequate for
  evaluating the severity of PTCitis

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Peritubular capillaritis in early renal allograft
is associated with the development of chronic
rejection and chronic allograft nephropathyAita
et al Clin Transplant 19 (Suppl.14)20-26 2005
ptc 1 (ACR)
ptc 2 (AbMAR)
ptc 3 (AbMAR)
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Peritubular capillaritis in early renal allograft
is associated with the development of chronic
rejection and chronic allograft nephropathyAita
et al Clin Transplant 19 (Suppl.14)20-26 2005
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Future Clinical Trials - PTC Data
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PTC mononuclear inflammatory cell accumulation
could reflect site of leucocyte trafficking

• Renkonen et al, Site of influx of inflammatory
  white cells into a rejecting rat renal allograft
  Transplantation 47577-579 1989
• Renkonen et al, Characterization of high
  endothelial-like properties of peritubular
  capillary endothelium during acute renal
  allograft rejection Am J Pathol 137643-651 1990
• Ivanyi et al, Postcapillary venule-like
  transformation of peritubular capillaries in
  acute renal allograft rejection. An
  ultrastructural study Arch Pathol Lab Med
  1161062-1067 1992

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PTC mononuclear inflammatory cell accumulation
could reflect upregulation of adhesion molecules

• VCAM-1 expressed on PTC endothelium in acute
  chronic rejection
• (Solez et al Adhesion molecules and rejection
  of renal allografts Kidney Int 511476-1480 1997)

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Chronic PTC Lesions

• Loss of endothelium basement membrane
  thickening / reduplication on PAS in CR
  (Mauiyyedi et al 2001)
• Moderate-severe basement membrane multilayering
  on EM associated with CR chronic Tx
  glomerulopathy (Monga et al 1990, Morozumi et al
  1997, Drachenberg et al 1997, Ivanyi et al 2000,
  Gough et al 2001, Vongwiwatana et al 2004)
• C4d deposition in subset of CR chronic humoral
  rejection (Mauiyyedi et al 2001, Regele et al
  2002, Ishii et al 2005)
• BM multilayering correlates with humoral
  mechanisms (Lajoie 1997, Takeuchi et al 2000)
  PTC C4d (Mauiyyedi et al 2000, Regele et al
  2002, Vongwiwatana et al 2004)
• Progressive injury, destruction loss in CR/CAN
  in association with progressive interstitial
  fibrosis (Bishop et al 1989, Shimizu et al 2002,
  Ishii et al 2005)

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3 years post-Tx, gradual rise in sCr, cv2 cg2
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3 years post-Tx, gradual rise in sCr, cv2, cg2
PTC BM multilayering
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Histological analysis of late renal allografts of
antidonor antibody positive patients with C4d
depositis in peritubular capillariesAita et al
Clin Tranplant 18 (Suppl.11)7-12 2004

• Evaluated PTCitis (using Banff 03 ptc score) in
  late allografts (gt1 year) with C4d
• antidonor Ab (n14)
• 7/14 had histologic features of CR (cg cv)
• PTCitis of varying severity observed in all 14
  cases ptc1 (n3), ptc2 (n5), ptc3 (n6)
• ptc score did not correlate with other Banff
  score
• PTC BM multilayering on EM found in 12/14
• Severity of multilayering did not correlate with
  ptc score

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Histological analysis of late renal allografts of
antidonor antibody positive patients with C4d
depositis in peritubular capillariesAita et al
Clin Tranplant 18 (Suppl.11)7-12 2004
ptc1
ptc3
ptc2
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Could peritubular capillaritis capillary
basement membrane thickening be the diagnostic
indicator of chronic rejectionAita et al Banff
2005 abstract

• Analysed late renal allograft Bxs (gt3 years
  post-Tx) from 53 patients for ptc score (as per
  Banff 03) for PTC BM thickening (using PAS)
• Compared ptc ptcbm scores in cases of CAN with
  without CR non-CR/CAN group, analyzed
  correlation between the two scores C4d staining
• The ptc ptcbm scores correlated significantly
  (plt0.001) both scores were highest in group of
  CAN with CR (in 23/27 cases, both scores were 2
  or 3)
• No correlation between ptc / ptcbm scores C4d
  staining
• Concluded that high ptc / ptcbm scores are highly
  suggestive of CR, and should be used as
  diagnostic criteria

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Peritubular capillaritis in early renal allograft
is associated with the development of chronic
rejection and chronic allograft nephropathyAita
et al Clin Transplant 19 (Suppl.14)20-26 2005
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3 years post-Tx, ptc2
IF C4d, weak diffuse
ICC C4d, focal PTC
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3 years post-Tx, ptc2
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3 years post-Tx, ptc2 PTC BM multilayering
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3 years post-Tx, PTC BM multilayering (up to 6
layers)
Serology shows anti-class II donor-specific
Ab (DQ6, titre gt164)
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Features of Chronic Humoral Rejection

• A constellation of findings, including
• - Peritubular capillaritis
• - PTC C4d deposition
• - PTC BM multilayering
• - Chronic Tx glomerulopathy
• Therefore ptc scoring would be helpful in this
  chronic context, as well as in acute stages of
  humoral rejection

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Peritubular Capillary Inflammatory Cell
Accumulation Scoring - Summary

• Assessment of PTCs in renal allograft pathology
  is important, and can provide useful diagnostic
  information
• The proposed PTC inflammatory cell accumulation
  (ptc) score is feasible, and there are compelling
  reasons for inclusion with established Banff
  scores
• Much more work is needed on the diagnostic
  significance of this lesion, and widespread
  application of the ptc score would facilitate
  that process