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									GRADING OF REJECTION IN
 PANCREAS ALLOGRAFTS
  Are changes needed?

   Cinthia B. Drachenberg, M.D.
  University of Maryland School of
              Medicine
           Baltimore MD
PANCREAS TRANSPLANTATION
BACKGROUND

   Insulin dependent diabetics (low C-
    peptide).

   13,000 pancreas transplants (1966-
    99).

   1200 in the USA in 1998.
PANCREAS TRANSPLANTATION
BACKGROUND


   1y patient survival 95%

   1y pancreas graft function 85%

   1y kidney graft function (SPK) 91%

Gruessner and Sutherland in: Clinical Transplants 1999,
  Cecka and Terasaki Eds. UCLA Immunogenetics Center,
  Los Angeles CA.
PANCREAS TX NEEDLE BX
BACKGROUND

   10 years since Allen et al.
    described the percutaneous biopsy
    technique (Transplantation
    1991;51:1213).

   > 550 done at the Univ. of MD
   Complications 2-3%.
PANCREAS TX NEEDLE BX:
INDICATIONS
   INCREASE IN SERUM AMYLASE/
    LIPASE
   HYPERGLYCEMIA
   UNEXPLAINED FEVER


   (DECREASE IN URINARY AMYLASE)
PANCREAS TX NEEDLE BX
BACKGROUND
   Minimum tissue amount adequate for
    diagnosis in a needle biopsy:

    Two lobules with associated septal tissue
     (arteries,veins, ducts).



   H&E stained sections x3
   Unstained slides
GRADING: ACUTE REJECTION
   Acute rejection starts in the septal area
    with venous endotheliitis. Vessels, acini
    and ducts are typically involved.

    (Carpenter et al. Sequential histopathologic
    changes in pancreaticoduodenal allograft
    rejection in dogs. Transplantation 1989;
    48:764)
GRADING: ACUTE REJECTION
0       No inflammation
I       Minimal septal inflammation
II      Venous endotheliitis
III     Acinar inflammation
IV      Arterial endotheliitis
V       Transmural arteritis
Drachenberg et al.: Transplantation 1997;63:1579.
GRADING OF REJECTION IN
PANCREAS ALLOGRAFTS



 Are changes needed?
Are changes needed?
   Grade I is non-specific with equal
    significance as grade 0.

   Simplification of the 5 grade system is
    desirable.

   The findings in pancreas rejection
    appear to be analogous to rejection
    Types I, II and III in the kidney.
      PROPOSED GRADING SCHEME

0     No inflammation          No rejection
I     Minimal septal infl.

II    Venous endotheliitis     Type IA
III   Acinar inflammation      Type IB

IV    Arterial endotheliitis   Type II

V     Transmural arteritis     Type III
       Correlation with response to
       treatment: 212 bx, 100 pt
TYPE     #    Treated   CS         CS/AL
0        90    42       39/13 (33%) 4/1(25%)

I A      51    47       34 (94%)   13 (85%)
  B      48    48       10 (80%)   38 (74%)

II A     15    14       2 (0%)     12 (78%)

III      8     8          -        8 (12.5%)
PANCREAS NEEDLE BIOPSIES
Differential Diagnosis
   Acute rejection
   Hyperacute rejection
   Pancreatitis – peripancreatitis
   Ischemia - thrombosis
   Viral infections (CMV, EBV-PTLD)
   Drug toxicity
   Recurrence of autoimmune disease
   Chronic rejection
GRADING OF CHRONIC
REJECTION IN NEEDLE BIOPSIES
   We had previously proposed a
    5 point histological grading
    scheme for the diagnosis of CR
    in pancreas transplant needle
    biopsies.
(Papadimitriou et al.Trans. Pro. 1999,
  31,614)
GRADING OF CHRONIC
REJECTION IN NEEDLE BIOPSIES

   PROGRESSIVE FIBROSIS.

   PROPORTIONAL ACINAR
    ATROPHY

   TRANSPLANT ARTERIOPATHY*
UPDATED CR GRADING SCHEME
   CR 0: No fibrosis
   CR I: Mild, Septal fibrosis in <30% of core
    surface.
   CR II: Moderate, Fibrosis in 30-60% of core
    surface.
   CR III: Severe, Fibrosis in >60% of core
    surface.

Acinar atrophy is proportional to fibrosis.
Transplant arteriopathy depending on sample.
UPDATED CR SCHEME:
CLINICAL CORRELATION
The average time from Bx to graft
 failure per grade:

   CR 0: 41 months
   CRI: 22.3 months
   CII: 10.8 months
   CIII: 1.2 m (p=.0001).
UPDATED CR SCHEME:
REPRODUCIBILITY
130 biopsies (Bx) from 36 randomly
  selected patients were analyzed blindly
  by 3 pathologists

   CR 0: k=.94 (p.0001)
   CRI: k=.79 (p.0001)
   CII: k=.85 (p.0001)
   CIII: k=.94 (p.0001)
UPDATED CR GRADING SCHEME
The proposed scheme correlates well
 with graft outcome and predicts to
 a large extent the remaining time
 of graft function.

The system is based on easily
 reproducible criteria.

								
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