GRADING OF REJECTION IN PANCREAS ALLOGRAFTS Are changes needed?

Cinthia B. Drachenberg, M.D.University of Maryland School of

MedicineBaltimore MD

PANCREAS TRANSPLANTATIONBACKGROUND

Insulin dependent diabetics (low C-peptide).

13,000 pancreas transplants (1966-99).

1200 in the USA in 1998.

PANCREAS TRANSPLANTATIONBACKGROUND

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 inflammationI Minimal septal inflammationII Venous endotheliitisIII Acinar inflammationIV Arterial endotheliitisV 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 IAIII 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 BIOPSIESDifferential 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.