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