Richard Smith Consultant Nephrologist Ipswich Hospital Beta cell replacement: Islet and whole...

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