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Richard SmithConsultant NephrologistIpswich Hospital
Beta cell replacement: Islet and whole pancreas transplantation
Whole pancreas usually transplanted as simultaneous kidney pancreas transplant
Should be considered for all patients with type 1 diabetes listed for kidney transplantation
Solitary pancreas transplantation also performed
May be pancreas transplantation alone (PTA)or pancreas after kidney transplant (PAK)
Indication is usually severe hypoglycaemia
Whole pancreas usually transplanted as simultaneous kidney pancreas transplant
Should be considered for all patients with type 1 diabetes listed for kidney transplantation
Solitary pancreas transplantation also performed
May be pancreas transplantation alone (PTA)or pancreas after kidney transplant (PAK)
Indication is usually severe hypoglycaemia
Islet transplantation is usually performed as islet transplant alone (ITA). May also be performed as islet after kidney transplant
Indication is severe hypoglycaemia
Figure 4a: Islet registrations by patient residence Figure 4b: Isolated pancreas registrations by patient residence
Registrations by Strategic Health Authority – Maps,1 February to 31 July 2011
* Three additional patients had overseas postcodes (including one from the Republic of Ireland)
Source: Transplant activity in the UK, 2010-2011, NHS Blood and Transplant
69
92 91
380
406
59 59
86
127
210
175
118
305
239
386
192
204
245
200
48
132145
322
206 216
90
11298
293
335
0
50
100
150
200
250
300
350
400
450
2001-2002 2002-2003 2003-2004 2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011
Year
Nu
mb
er
Donors
Transplants
Transplant list
Deceased pancreas and islet programme in the UK, 1 April 2001 - 31 March 2011Number of donors, transplants and patients on the active transplant list at 31 March
Bristol
Manchester
Newcastle
Royal FreeKings
Oxford
Edinburgh
Single allocation scheme for wholepancreas and islet transplantation
3 Indications for pancreas transplant alone3.1 CriteriaPresence of insulin dependent type 1 diabetes mellitus
Significant diabetic complications
Life threatening complications ie frequent and severe episodes of hypoglycaemia
Hypoglycaemia unawareness
Impairment of quality of life
Other metabolic or behavioural problems causing referral by a diabetologist
Indications: PTA
3 Indications for pancreas transplant alone3.1 CriteriaPresence of insulin dependent type 1 diabetes mellitus
Significant diabetic complications
Life threatening complications ie frequent and severe episodes of hypoglycaemia
Hypoglycaemia unawareness
Impairment of quality of life
Other metabolic or behavioural problems causing referral by a diabetologist.
Indications: PTA
Indications: ITA
Severe hypoglycaemia
Two or more episodes of hypoglycaemia requiring outside help in the previous 6 months
Hypoglycaemia unawareness
Outcomes: UK SPK 1 April 2003 to 31 March 2009
% p
atie
nt s
urvi
val
40
50
60
70
80
90
100
years post-transplant0 1 2 3 4 5
% g
r aft
surv
i val
40
50
60
70
80
90
100
years post-transplant0 1 2 3 4 5
% Survival (95% CI) N 1 Year 3 Year 5 Year 03/04-04/05 114 82 (74-88) 75 (66-82) 72 (63-80) 05/06-06/07 249 89 (84-92) 85 (79-89) 07/08-08/09 294 88 (83-91)
N % Survival (95% CI) 1 Year 3 Year 5 Year 03/04-04/05 114 95 (89-98) 90 (83-95) 86 (77-92) 05/06-06/07 250 94 (90-96) 91 (86-94) 07/08-08/09 296 96 (93-98)
Pancreas graft survival Patient survival
Outcomes: UK PTA/PAK 1 April 2003 to 31 March 2009
% g
raft
surv
ival
0
10
20
30
40
50
60
70
80
90
100
years post-transplant0 1 2 3 4 5
% p
atie
nt s
urvi
val
0
10
20
30
40
50
60
70
80
90
100
years post-transplant0 1 2 3 4 5
Pancreas graft survival Patient survival
N % Survival (95% CI) 1 Year 3 Year 5 Year 03/04-04/05 15 67 (38-85) 60 (32-80) 47 (21-69) 05/06-06/07 38 76 (59-87) 57 (40-71) 07/08-08/09 55 76 (62-85)
N % Survival (95% CI) 1 Year 3 Year 5 Year 03/04-04/05 15 100 (-) 100 (-) 90 (43-98) 05/06-06/07 39 97 (83-99) 94 (78-99) 07/08-08/09 56 94 (83-98)
Islet transplantation: Bristol
3 Patients
1 achieved insulin independence with first transplantAcute graft failure 3 months post transplant
1 achieved complete resolution of hypoglycaemic for 1 yearReduction in insulin doseHas now received pancreas transplant
1 achieved resolution of hypoglycaemia with one transplantSecond transplant 14.2.10 achieved insulin independenceRemains insulin independent
UK Outcomes54 islet infusions in 34 recipients27 ITA 6 IAK 1 SIK1 infusion n=16 2 infusions n=16 3 infusions n=296% graft function at one month Severe hypoglycaemia reduced by >95% HbA1c reduced (8.4% vs 7.0%)
International Outcomes (www.citregistry.org) 1072 infusions in 571 recipients1 infusion 31% 2 infusions 47% 3 infusions 20% >3 2%Graft survival 40-80% five years70% patients free of severe hypoglycaemia at 1 year18 deaths over mean of 6 years follow up
Hypoglycaemia
NE001
NE002
NE003
NE004
NE010
KC001KC002
KC003KC004
OB1
OX001
OX003
OX006
OX011
OX019
OX021BR101
RF002
RF003
RF004
MA002ED
001
0
10
20
30
40
50
60
70
Annual hypos pre
Annual hypos post
Annu
al h
ypo
rate
In ‘typical’ month
1 patient admitted to GRH with acute abdomen
1 patient admitted to Moreton in the Marsh with chest pain
1 patient admitted to Cheltenham with chest pain
1 patient joint care with obstetrics
1 patient joint care with urology
3 patients referred for gastroenterology opinion
1 patient referred to pain clinic (peripheral neuropathy)
Summary of tests to assess function
FPG/RBG/HbA1c
75g Oral Glucose Tolerance Test
Mixed Meal Tolerance Test
Arginine Intravenous Glucose Tolerance Test
Patient OGTT HbA1c (%) Fasting Glucose (mmol/L)
3 m 12 m 3 m 12 m 3 m 12 m
1 (SPK) 5.5 5.6 5.8 5.1
2 (PAK) 4.4 5.1 4.7 4.6
3 (PTA) 5.1 5.1 4.5 4.7
4 (PTA) 5.2 5.3 4.0 4.1
5 (SPK) 5.6 5.7 6.2 5.5
6 (PAK) 5.8 6.0 4.8 5.8
Outcomes: Glycaemic control
Patient OGTT HbA1c (%) Fasting Glucose (mmol/L)
3 m 12 m 3 m 12 m 3 m 12 m
1 (SPK) NGT NGT 5.5 5.6 5.8 5.1
2 (PAK) NGT NGT 4.4 5.1 4.7 4.6
3 (PTA) NGT NGT 5.1 5.1 4.5 4.7
4 (PTA) NGT NGT 5.2 5.3 4.0 4.1
5 (SPK) IGT IGT 5.6 5.7 6.2 5.5
6 (PAK) DGT DGT 5.8 6.0 4.8 5.8
85% of patients have normal OGTT at 1 year post
transplant
Outcomes: Glycaemic control
0 20 40 60 80 100 120 1400
2
4
6
8
10
12
14
16
0
50
100
150
200
250
19
46
102
41
64
45
5.3
6.7
9.1
5.3
6.6 6.3
Glucose (mmol/L) Insulin (mIU/L)
Time (minutes)
Gluc
ose
(mm
ol/L
)
NGT
Outcomes: Glycaemic control
-30 -10 10 30 50 70 90 110 130 150 17002468
101214161820222426
0
200
400
600
800
1000
1200
1400
Pancreas Tx Patient IVGTT at 3 months
Glucose (mmol/L) Insulin (pmol/L)
Time (minutes)
Gluc
ose
(mm
ol/L
)
Insu
lin (p
mol
/L)
-30 -10 10 30 50 70 90 110 130 150 17002468
101214161820222426
0
200
400
600
800
1000
1200
1400
Pancreas Tx Patient IVGTT at 3 months
Glucose (mmol/L) Insulin (pmol/L)
Time (minutes)
Gluc
ose
(mm
ol/L
)
Insu
lin (p
mol
/L)-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160
02468
101214161820222426
0
20
40
60
80
100
120
140
160
180
200
Patient 3 - IVGTT 3 months after 2nd Tx
Glucose (mmol/L) Insulin (mIU/L)
Time (minutes)
Gluc
ose
(mm
ol/L
)
Insu
lin (p
mol
/L)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
-50
0
50
100
150
200
Outcomes: Beta cell function
Acute insulin response to glucose
Acute insulin response to arginine
Arginine intravenous glucose tolerance test 3 months post transplant
IsletDysfunction
Functioning Islets
PancreasDysfunction
FunctioningPancreas
Diabetes
Insulin Independence
Baidal et al, Transplantation 2009, 87(5): 689-697.
Miami Islets PancreasMMTT DysF (n=9) F (n=5) AbNGT (n=3) NGT (n= 15)Basal Glucose 6.1 5.7 5.1 4.7Basal C-peptide 456 486 357 52690 min Glucose 8.5 6.9 7.5 5.890 min C-peptide 999 1038 1477 1470
IVGTT AIR glucose 10.3 20.5 34.4 58.7AIR arginine 21.6 24.4 39.8 53.4
Miami Islets Bristol IsletsMMTT F (n=5) DysF 2 (n=9) Patient 2 Patient 3Basal Glucose 5.7 6.1 6 5.8Basal C-peptide 486 456 218 14890 min Glucose 6.9 8.5 12.2 7.790 min C-peptide 1038 999 828 531 IVGTT AIR glucose 20.5 10.3 -0.7 3.2AIR arginine 24.4 21.6 14.2 12.4
-30 0 30 60 90 120 150 1800
5
10
15
20
25
Insulin 3 Insulin 6 Insulin 9 Insulin 12
Time (minutes)
Acut
e In
sulin
Res
pons
e (A
IR)
Arginine Glucose
Pancreas Transplantation ?
Islet Transplantation ?
May not work!
International and UK outcomes support whole pancreas transplantation
International results support islet transplantation
UK results support islet transplantation also
Patients presented clearly benefitted
These results are from early phase of program
At this time not ticking boxes associated with good outcome
Islet versus whole pancreas transplant ?
Risk aversity
Comorbidity
Whole PancreasIslet
Neither whole pancreas or islet transplantation are best for all patients
Choice is predicated on being able to achieve successful islet transplantation
UK islet transplant outcomes are now good enough to justify islet transplantation’s place alongside whole pancreas transplantation
Primary indication the same: severe hypoglycaemia
Islet transplant for the more risk averse patient or patient with comorbidity precluding whole pancreas transplantation
Whole pancreas transplantation may be preferable for the patient in whom additional benefit might accrue from better more sustained glycaemic control
Further information
Diapedia
Islet transplantation – an overview 2014 Diapedia 81040851399 Rev no 4 Available from http://dx.doi.org/10.14496/dia.81040851399.4
Pancreas transplantation 2014 Diapedia 81040851381 Rev no 6 Available from http://dx.doi.org/10.14496/dia.81040851381.6
Also:www.clinimeded.co.uk