Sum Scores

1
Sum Scores Components ScoresChronic
ScoresAcute Rejection ScoresLillian W.
GaberUniversity of Tennessee
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Too Many or Less Features to Evaluate
Reproducibility
Clinical Relevance

• Inclusive but in the mean time selective of the
  examined lesions
• Weigh lesions according to their importance

• Simplify the schema
• less features to assess
• Conspicuous lesions

3
Definitions of Acute Rejection and Clinical
Correlation

• Mild AR Mild cellular rejection
• Moderate Cellular rejection with glomerulitis or
  mild vasculitis
• Severe Extensive diffuse cellular or vascular
  rejection and cases with thrombosis, RBC
  extravasation or necrosis
• Irreversible Extensive necrosis and infarction
• Banfi et al 1981

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Definitions of Acute Rejection and Clinical
Correlation
Mild rejection Interstitial edema and minimal
infiltrates Moderate rejection More extensive
infiltrate evidence of glomerular or vascular
changes Severe rejection the above with necrosis
or infarction Finkelstein et al, 1976
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Early Studies with Semiquantitative Data

• Hsu et al- University of Toronto (1976)
• Chronic lesions, fibrinoid vascular deposits and
  obliterative endarteritis correlate with
  creatinine rise at 1-3 mo post biopsy
• Klaer et al- Aarhus Denmark (1980)
• Glomeurlar or arterial thrombosis and infarction
  correlate with graft loss
• Banfi et al- Milan (1981)
• Glomerular necrosis, intimal arteritis, arterial
  fibrinoid necrosis and PTC congestion predicted
  elevation of the 2-mo postbiopsy creatinine
• Durand et al, France (1983)
• Arterial and tubular lesions were the strongest
  predictors of adverse outcome
• Parfrey et al, McGill University (1984)
• Interstitial hemorrhage was the strongest
  predictor for graft failure. Intimal arteritis
  and glomerulitis strengthened the prognosis

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Acute Rejection Index(0-36)

• Glomerular endothelial swelling
• Endothelial and mesangial proliferation
• Glomerular Leukocytes
• Glomerular necrosis
• Interstitial edema
• Interstitial inflammation
• Swelling of the vascular endothelium and edema
• Mural vascular inflammation
• Mural vascular necrosis

FinkelsteinKashgarian 1976
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Finkelstein et al, 1976
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Scoring of Lesions in Renal Allograft Biopsies

• Interstitial Infiltration
• mild and focal
• severe but focal
• diffuse
• Arterial Lesions
• endothelial swelling
• intimal proliferation fibrinoid necrosis
• subtotal occlusion or thrombosis

• Tubular Lesions
• 25-50
• 50-75
• 75-100
• Infarction
• PTC congestion
• interstitial space infarction
• diffuse necrosis
• Interstitial Edema
• Venous Dilatation

Durand et al , 1983
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Semiquantitative Evaluation of Histologic Lesions
and Outcome
Durand et al , 1983
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Scores Predicting Graft Outcome

• Discriminative analysis of the major histologic
  features for their effect on prognosis the
  generation of a linear combination
• (0.66 x infiltrate score) - (1.98 arterial score)
  - (0.42 edema score) - (1.28 tubular score) -
  (0.78 infarction score) 3.21
• When the combination was positive, the outcome
  was favorable in 83 of patients i.e. one year
  serum creatinine.
• Durand et al , 1983

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Banff 97/CCTT Grading of Acute Rejection
with at least i1 and 2 or more of the following
features edema, activated lymphocytes or tubular
injury
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Questions!

• Is the current grading of rejection clinically
  relevant?
• Do Grades and scores correlate with clinical
  severity?
• Are grades/scores helpful in managing patients
  outside of study protocols?
• How were scores used in clinical trials and
  investigative research?
• Is there a need to modify the current scores, and
  if so how to do it?

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Did we do better with Banff Schema than
descriptive terminology
Dean, Cavallo et al 1999
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Interpretation by Standardized Banff Schema is
Superior to conventional non-standardized
diagnoses
Over-readlower scores were assigned by Banff
than previous diagnosis
Dean, Cavallo et al 1999
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Outcome of Patients
Dean, Cavallo et al 1999
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CCTT Analysis of Morphologic Correlates to
Clinical Severity of Acute Rejection

• Morphologic features that significantly
  correlated with clinical severity of rejection
• Type II rejection
• Tubular injury
• Endothelialitis
• Interstitial hemorrhage
• Interstitial edema
• Glomerulitis
• Activated lymphocytes
• Tubulitis

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Vascular Scores
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Validity of Banff 93 Schema in Clinical
Practice- University of Tennessee

• Correlation between the sum scores and grades of
  acute rejection
• Borderline (Sum 1.6 0.5)
• Grade I (Sum 3.3 0.4)
• Grade II (Sum 4.2 0.3)
• Grade III (Sum 8.5 0.4)
• Grades correlate with rejection reversal
• Complete reversal occurred in 93 of Grade I
• 47 of Grade III were irreversible
• Resistance to steroids and reversal of rejection
  correlate with the vascular scores

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Impact of Vascular (Type II)/Cellular (Type I)
Rejection in the First 3 months on Long Term
Graft Survival
Van Saase et al, 1995
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Divergent graft survival between
tubulointerstitial rejection and rejection with
fibrinoid necrosis
P 0.03 versus Type I
Nickeleit, Colvin et al, 1998
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Av- Type of Vascular Pathology
Nickelett Colvin 1998
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Vascular Pathology and Rejection Outcome

• Number of arteries with lesions did not correlate
  with steroid responsiveness or the 12-month
  creatinine
• Of the different types of lesions, reactive
  endothelium and sticking of mononuclear cells
  correlated with steroid resistance

Nickelett Colvin 1998
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Scores of Pathologic Features of Acute Rejection
the risk of graft failure
Mueller et al 2000
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Vascular Scores

• The most significant determinant of steroid
  response, rejection reversal and kidney function
  at one year
• Vascular rejection is a predictor of chronic
  rejection
• Number of arteries to be examined?
• Isolated vascular rejection?
• V1-2 rejection and severe tubulo-interstitial
  rejection?
• Lumen compromise and severity of rejection?
• Sticky mononuclear cells and endothelial edema?
• Fibrinoid vascular necrosis! Rejection or no
  rejection?

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Interstitial scores
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Interstitial infiltratesThreshold for Acute
Rejection

• i1 in Banff identified as 10-25 of parenchyma
  involved
• Type I rejection Banff requires at least i1
• CCTT specified greater than 5 inflammation in
  the renal cortex

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Extent of Interstitial Infiltrate Rejection
Grade
Nickelett Colvin 1998
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AI- Extent of interstitial infiltrates and outcome
Nickelett Colvin 1998
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Interstitial inflammation/infiltration Variables

• Cell Types in the interstitial infiltrates
• Activated lymphocytes
• Monocytes
• Plasma cells
• Eosinophils
• Surface area involved
• Edema

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Tubular Injury Scores
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Acute tubular injury

• CCTT group identified tubular injury as a
  significant parameter in determining severity of
  acute rejection
• Tubulitis scores tended to be higher in patients
  with OKT3 failure, and identified higher T scores
  for partially reversed and irreversible rejection
  compared to completely reversed rejection- UT
• Mild or moderate tubulitis (Banff 97 IA) have
  better prognosis than acute cellular rejection
  with severe tubulitis (Banff 97 IB). No
  differences between acute rejection with t3
  (Banff IB) and rejection with mild vasculitis v
  1(Banff IIA) in terms of rejection reversal,
  12-month creatinine or graft loss. Randhawa, AST
  2000

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Scores for Tubulitis

• Post rejection biopsy scores
• Severe tubulitis with very mild inflammation
• Acute tubular necorsis tubulitis

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Acute Glomerulitis Scores
34
Glomerulitis

• Kashgarian recognized the significance of
  endothelial swelling and glomerular inflammation
  alongside with vascular pathology
• Scores for G were higher in the irreversible and
  partially reversible rejection, and in steroid
  resistant rejection. Higher glomerular scores for
  patients with recurrent rejections (NS). UT
• Glomeruliits more in first rejection, patients
  with delayed graft function and has worse outcome
  than G0 rejection. Racusen AST, 2000
• Glomerulitis distinguished patients with Bo that
  progressed to rejection

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Glomerulitis Scores

• Glomerulitis and Antibody-mediated rejection
• Glomerular necorsis and thrombosis in TMA
• Is it a sign of a unique or a severe rejection?

36
Scores and Sum Consensus
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Sum scores in Clinical Practice

• Excellent correlation between grades of rejection
  and response to therapy, outcome parameters
• Although scores in most cases correlate the grade
  of rejection, they are not to be used for
  therapeutic decisions
• Incorporation of scores in the reports is
  optional, but highly recommended for data
  accession and retrieval in academic centers
• Inclusion of scores and sum of rejection is
  encouraged
• Forces compulsive and methodical analysis of the
  morphologic features
• Easy method to scan the pathology report for
  rejection severity in the different compartments

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Sum Scores in Clinical Trials

• It is strongly recommended for clinical trials
  for meaningful statistical analysis of
  morphologic features
• Potential application in clinical trials
• Fibrosis at 6 mo-2 years is an appropriate
  surrogate endpoint in chronic rejection trials
• Not necessary for inclusion, but they may be
  important to thoroughly compare both arms in a
  study
• Endpoint analysis
• Control sample size and followup period

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Vascular scores

• Need 4 arteries to increase the sensitivity for
  the detected of intimal arteritis
• Number of arteries affected by inflammation does
  not impact therapy response or graft survival
• Adhesion of mononuclear cells to activated
  endothelium correlates with steroid failure.
  Should we add suspicious for acute vascular
  rejection or include it with Type IIA. Type IB
  and IIA act similarly!

40
Glomerulitis

• Underdiagnosed entity
• Highly associated with Ab-mediated rejection and
  feature of borderline progressing to acute
  rejection. May identify a subset of acute
  rejection. May be the predecessor for chronic
  transplant glomerulopathy
• Should we use CD68?

41
Tubulitis

• Rejection with severe tubulitis acts similar to
  mild vascular rejection

42
Interstitial Inflammation

• Continue to specify and flag cell types
• Mononuclear cell score?

43
Chronicity scores

• Interstitial fibrosis
• Recommend evaluation by trichrome/sirius red
• Morphometric assessment for studies is
  recommended
• Chronic transplant vasculopathy
• Types
• Inactive sclerosing transplant vasculopathy
• Proliferative sclerosing vasculopathy
• Foam cell
• Elastic stains or conventional stains adequate?
• Chronic rejection with TV is more aggressive.
  Socres for RTV may need to be adjusted?
• Glomerular pathology specify obsolescent/solidifie
  d/FSGS

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C4D Staining

• Do we need to incorporate in the sum?
• What is the value to be assigned?

45
Sum Scores

• Not ideal to represent the rejection severity or
  reflect on the pathogenesis of rejection. Linear
  parameter and does not take into account the
  varying relative strength of its components in
  the assessment of rejection severity
• Design a more mathematically correct parameter?
• Combined clinical and Morphological index?

46
Scoring of lesions in renal allograft biopsies
Durand et al

• Interstitial Infiltration
• mild and focal
• severe but focal
• diffuse
• Arterial Lesions
• endothelial swelling
• intimal proliferation fibrinoid necrosis
• subtotal occlusion or thrombosis

• Tubular Lesions
• 25-50
• 50-75
• 75-100
• Infarction
• PTC congestion
• interstitial space infarction
• diffuse necrosis
• Interstitial Edema
• Venous Dilatation

Durand et al , 1983
47
Frequency of Lesions and Outcome
Durand et al , 1983
48
Semiquantitative Evaluation of Histologic Lesions
and Outcome
Durand et al , 1983
49
Scoring of lesions in renal allograft biopsies
Durand et al

• Discriminative analysis of the major histologic
  features for their effect on prognosis lead to
  the generation of a linear combination
• (0.66 x infiltrate score) - (1.98 arterial score)
  - (0.42 edema score) - (1.28 tubular score) -
  (0.78 infarction score) 3.21
• when the combination was positive, the outcome
  was favorable in 83 of patients i.e. one year
  serum creatinine.
• Durand et al , 1983