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ISLET TRANSPLANTATIONTHE EDMONTON EXPERIENCE
Angela KohKhoo Teck Puat Hospital , Singapore
OVERVIEW
Brief Review of Islet Transplantation
Improving outcomes
Effect on diabetes complications
Future directions
GOAL OF THERAPY
WHY ISLET TRANSPLANTATION?
PANCREAS TRANSPLANT
WHO IS A CANDIDATE?
WHO IS A CANDIDATE?
KEY INDICATIONS FOR ISLET TRANSPLANTATION
Hypoglycemia +/- hypoglycemia unawareness ~75%
Glycemic lability ~25%
OTHER CRITERIA
Type 1 DM
Weight < 90 kg and BMI <30
Insulin use < 1 unit/kg
C-peptide minimal
GFR>60
Stable retinopathy
Not on anticoagulation
HERALDING A NEW ERA...
EDMONTON PROTOCOL V.1
Immunosuppression regimen:
Induction: Daclizumab (IL-2 receptor antagonist)
Maintenance:
Sirolimus + Tacrolimus
Steroid free
Freshly isolated islets, 10 000 IEQ/kg
Insulin stopped immediately after tx, resumed only if hyperglycemic
Islet Transplant Ac.vity (1999-‐2008)
Edmonton (102) Miami (47) Minneapolis (25)
Vancouver (26) U Penn, (17) Houston (13) Harvard, Boston (13)
Birmingham AL (3) Northwestern, (11) St. Louis (9) U Illinois (11) Emory, Atlanta (9) Cincinna. (6) NIH (6) SeaSle (6) City of Hope CA (5) Memphis (3) U Maryland (2) Columbia NY (2) U Mass (2) UC San Francisco (9) Carolina Med Center (1) Cornell NY (3) Denver (1)
San.ago Chili (1) San Paulo (3) Buenos Aires (11)
Sydney (6) Kyoto (6) Tokyo (1) Seoul (2) Chiba (1) Harbin (1) Shanghai (1)
> 50 Ins.tu.ons: > 660 pa.ents
NORTH AMERICA
EUROPE
SOUTH AMERICA
ASIA & AUSTRALIA
Geneva+GRAGIL (75) Milan (54) Giessen (31) Brussels/Free Univ (25) Nordic Network (25) Brussels/Louvain (20)
Lille (26) Budapest/Geneva (3) King’s UK (4) Royal Free UK (3) Oxford (1) Stockholm/Giessen (2) Nantes (1)
Zurich (12) Innsbruck (11)
Approximately 60 islet infusions in 2007 (45 in N America, 15 in Europe)
CHALLENGES
Insulin independence with single donor uncommon
Progressive loss of graft function over time
Alloimmune + Autoimmune
Other metabolic factors?
Side effects of procedure
Side effects of immunosuppression
Improving Outcomes of Islet Tx.022
SINGLE DONOR INSULIN INDEPENDENCE
42.1%
7.6%
p<0.001
p=0.046
73%
BURST BUBBLE? PROGRESSIVE LOSS OF GRAFT FUNCTION
C-peptide positive
Insulin Independence
Corrected HbA1C and absence of hypoglycemia
18%
% S
urvi
val
Time (Months) 0 12 24 36 48 60 72 84 96 108 120
0
20
40
60
80
100
SPK PANCREAS GRAFT SURVIVAL
PAS ACMLT.050
Metabolic Tests vs Protocol
Campath Edmonton Infliximab Alemtuzumab
Protocol
0
20
40
60
80 Arginine
IVGTT
(3/71) (8/71)
(3/9)
(1/9)
(6/7)
(4/7)
(1/10) (0/10)
Percen
t Pa.
ents with
Normal M
etab
olic Respo
nse 100
Improving Outcomes of Islet Tx.032
IMPROVING TOLERABILITY
SIDE EFFECTS IMPROVE WITH SWITCH FROM SIROLIMUS + TACROLIMUS TO TACROLIMUS + MMF
0 25 50 75 100 125
Oedema
GI Symptoms
Ovarian Cysts
Fatigue
Ulcers
Proteinuria
PercentageImproved No Change/worse
n=34
EFFECTS ON DM COMPLICATIONS
0.0
12.5
25.0
37.5
50.0
Improve ≥ 3 steps Improve< 3 steps No change Worse< 3 steps Worse ≥ 3 steps
% o
f pat
ient
s CIT Control
Changes in Retinopathy by eye at 5 years
p=ns
CIT n = 63; Controls n = 9
Ocular Events after CIT
11 5
2
Vitreous Hemorrhage PRP for worsening DR Focal Laser for maculopathy
• 18 of 98 patients (18.4%) had at least 1 significant ocular event post-CIT.
PERIPHERAL NEUROPATHY
1
4
7
10
13
Pre 1 year 2 years 3 years 4 years 5 years 6 years 7 years
HbA1c NDS VPT
Al-baker, Koh, Senior. JCEM Suppl 2008
RENAL FUNCTION DECLINES POST-TRANSPLANT
Impact of IS on renal function
NEW OR WORSE CAD DEVELOPS AT A RATE SIMILAR TO THE GENERAL TYPE 1 DIABETES
POPULATION
Study Follow-up Duration (years)
CAD Event Rate (event/1000 patient
years) Islet transplant 4 11
EURODIAB Prospective Complications study
7 9.3
Pittsburgh Epidemiology of Diabetes Complications study
10 7
DCCT/EDIC Intensive group
17 3.8
Koh et al, Diabetes Suppl 2008
WHAT’S AHEAD
PAS ACMLT.060
DEFINING SUCCESS
Insulin Free
Good Glycemic
Control
No DMComplications
Acceptable
Risks
Tolerable
SEs
PRE-TRANSPLANT
1-MONTH POST TRANSPLANT #1
1-YEAR POST TRANSPLANT #2
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