Surveillance Biopsies in Transplantation Premise

1
(No Transcript)
2
Subclinical Rejection In Pancreas Protocol
Biopsies

• Lillian Gaber
• University Of Tennessee, Memphis

3
Surveillance Biopsy Protocol At UT

• Surveillance biopsy protocol for pancreas alone
  or pancreas after kidney transplants
• Adopted from the Nebraska protocol
• Graft surveillance by biopsies done during the
  first 4 mo post transplantation

4
Surveillance Biopsies In CsA Era

• Cystoscopic transduodenal biopsies (n50) in 24
  patients at 1, 2, 3, 6 and 12 Mo
• Rejection episodes, except one, were treated
• Rejection was graded mild, moderate or severe
• Mild subclinical rejection in 26 of protocol
  biopsies in the first 6 months posttransplanation
• Recurrent clinical acute rejection in 2 Mo
• 60 of patients with positive protocol biopsies
• 15 of patients with negative protocol biopsies

Stratta et al Transplantation 1995
5
Actuarial Survival of Patients and Solitary
Pancreas Grafts
Stratta et al Transplantation 1995
6
Subclinical Rejection In Solitary Pancreas With
And Without Induction

• Induction with OKT3, daclixumab or thymoglobulin
• Protocol biopsies 7 days post induction, at 2-3
  mo and at 1 year
• Occult rejection in 22 biopsies during the first
  3 months
• No impact of induction

Larson et al Transplantation 2001
7
Solitary Pancreas Protocol BiopsiesMayo Clinic
Casey et al Transplant 2005
8
Sublincial Rejection In SKP Transplants

• Subclinical rejection in either kidney or
  pancreas allografts
• 58 day 21
• 61 day 40
• 13 AT 1 year
• Concordance between kidney and pancreas
  subclinical rejection in 47

Kuhr et al J Urol 1995 Marsh et al
Transplantation 2001
9
Surveillance Biopsy Protocol- UT

• Surveillance biopsies are routinely performed for
  patients with solitary pancreas transplants (PA
  and PAK)
• First biopsy at 2 wk, then 3 more biopsies at
  4-weeks intervals (1-4 mo)
• Antirejection therapy administered if protocol
  biopsy is positive for acute rejection (Grade
  II-V)
• Follow-up biopsy is performed within 2 weeks
  after completion of therapy

10
Immunosuppression

• Induction Immunosuppression
• OKT, Thymoglobulin, Zenapax
• Maintenance Immunosuppression
• Pred, FK506, MMF

11
Sureillance Biopsies Protocol

• Percutaneous needle biopsies under ultrasound
  guidance
• Routine light microscopy
• HE and PAS-H
• Retrospective IHC
• Phenotype inflammatory cells
• CD68, CD3, CD4, CD8, CD20
• Granzyme
• Histone B

12
Grading Of Acute Rejection (University Of
Maryland Schema)

• Grade 0- Normal
• Grade I- Inflammation of Undetermined
  Significance
• Grade II- Minimal Rejection
• Grade III- Mild Rejection
• Grade IV- Moderate Rejection with intimal
  arteritis
• Grade V- Severe Rejection (confluent necrosis or
  diffuse acinar inflammation)

13
Surveillance Biopsies In 32 PA And PAK
Transplants In Tacrolimus Era
14
Acute Rejection in Pancreas Allograft Protocol
Biopsies
15
Acute Rejection In The First Month

• 13/32 biopsies with acute rejection (42)
• Grade II-III (n9)
• Grade IV-V (n4)
• Graft type
• PA (n6)
• PAK (n7)
• Treatment outcome according to BX2
• Persistent rejection same or increased grade
  (n4 31)
• Improved but incomplete resolution of
  inflammation (n5 4 improved to IUDS)
• Resolution of rejection (n4)

16
Subclinical Acute Rejection
17
GL24

• 37 year-old, man
• PA
• 3-HLA mismatched pancreas from a 27 year-old
  donor
• (R CMV, D CMV-) CIT was 21 hours.
• Zenapax induction
• First protocol biopsy (2-week)
• Grade II treatment with 3 pulses of Solumedrol
• BX2
• Grade II Zenapax and FK levels were readjusted
• Subsequent protocol biopsies (Bx3 and Bx4)
  negative IUDS
• Normal function at 1 1/2 year

18
GL24-2 wk protocol biopsy
19
GL-2 wk protocol biopsy
Granzyme
CD8
20
DF197

• A 41year-old, female
• Previous failed SPK, and a second kidney
  transplant
• PAK
• OKT3 induction
• Day 15 surveillance
• Grade IV acute rejection on treated with
  Solumedrol
• BX2
• Improved rejection (IUD, with mild enzyme
  elevation) and evolution of fibrosis
  Thymoglobulin treatment
• BX3 no rejection, mild fibrosis
• Incidental intraoperative biopsy (2-years)
  normal
• Patient has functioning graft at 3 years

21
DF-Day 16 Surveillance Biopsy
22
DF-Day 16 Surveillance Biopsy
23
DF-Day 16 Surveillance Biopsy
CD68
Tcell
24
CG249

• 28 year old female
• Pancreas alone
• ATG induction
• BX1-2wk
• Grade III rejection
• Amylase and lipase levels (39 IU/dl and 18.8
  ng/dl)
• OKT3 therapy
• Bx 2
• Grade III rejection with clinical dysfunction
• Diagnostic biopsies at 3, 4 and 5 mo persistent
  mild acute rejection and progression of chronic
  rejection
• Pancreatectomy at 5 months

25
CG249-2wk Surveillance
26
CG-2wk Surveillance
27
CG-2wk Surveillance
28
CG-Day 19 Surveillance
CD68
CD8
Granzyme
29
IUD Or Rejection

• LM a 39 year old male, second PAK
• Zenapax for induction
• Bx1 IUDS
• BX2 Grade III acute rejection
• Bx3 Grade IV acute rejection
• Bx4 IUDs
• Functioning pancreas for 5 years

30
LM342- IUDS Or Rejection
31
LM342- IUDS Or Rejection
32
LM342- IUDS Or Rejection
CD8
CD4
Granzyne
CD68
33
MC600- IUDS Or Rejection
CM 38 year old female with PA No follow up
34
IUDS Or Rejection Or Not
CD8
CD68
35
KB467- Rejection Or Pancreatitis

• 38 year old
• Bx1 day 15 biopsy
• acute pancreatitis, fat in pancreas, and
  suspected rejection. Retrospective IHC performed
• Bx2
• Severe cellular rejection (III or V)
• Bx3
• Resolution of rejection and fibrosis
• Graft functioning at 5 years

36
BK467-Day 15 Surveillance Rejection Or
Pancreatitis
37
BK467-Day 15 Surveillance
CD8
CD68
38
Surveillance Biopsy Monitoring Of Solitary
Pancreas Allografts

• Surveillance biopsy protocol identify subclinical
  rejection before clinical evidence of graft
  dysfunction
• Subclinical rejection is common in the first 1
  month post transplantation
• Surveillance biopsies can determine efficacy of
  immunosuppression protocols
• Early treatment of subclincal rejection appears
  beneficial. Larger number of cases needed as well
  as controlled studies? Are needed
• Immunohistochemistry is useful to evaluate
  questionable cases and borderline findings.

39

• Are we underestimating inflammation and injury by
  doing only light microscopy?
• Should IHC be performed and what are the
  appropriate set ups?
• Which activation markers to use?
• Apoptosis and who to measure?

40

• 45 patients with solitary pancreas transplants
  had no protocol biopsies graft failure rate was
  64
• 23 patients with solitary pancreas transplants
  monitored by surveillance biopsies, graft failure
  rate was only 22

41
(No Transcript)