Astellas, Sanofi Sandoz, Roche, IGLcuen.fr/powerpoint/seminaire_decembre2018/16...Islet graft Diapo...

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Stratégie de transplantation chez le patient diabétique de type 1

Transplantation strategy in Type 1 diabetic patient

Emmanuel Morelon

Service de Transplantation, Néphrologie et Immunologie Cliniqu eHôpital Edouard Herriot – LYON

Inserm U 1111

Actualités Néphrologiques Jean HamburgerHôpital Necker23 avril 2018

Disclosure

� Advisory Boards : Novartis, Chiesi, Astellas, Sanofi

� Symposium: BMS, Sanofi, Astellas, Chiesi, Sandoz, Roche, IGL

� Research grants: Novartis, Astellas, Chiesi

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Case report 1� Female 42 years old

� Type 1 diabetes

� Diabetes duration: 24 years

� Hb A1C 8.5% Insulin therapy: Implantable pump

� Hypoglycemia: once a day, no severe hypoglycemia

� Diabetes complication: neuropathy, retinopathy, nephropathy

� GFR : 44 ml/mn/1.73m2 (CKD EPI)

� Blood Group: AB

� No evidence for macroangiopathy

Case report 1: which transplantation ?

� Pancreas transplantation ?

� Islet transplantation ?

� Simultaneous pancreas kidney transplantation ?

� Simultaneous islet kidney transplantation ?

� Kidney transplantation followed by pancreas after kidney ?

� Kidney transplantation followed by islet after kidney ?

� No transplantation, optimal insulin therapy and nephroprotection ?

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� Type 1 diabetes


� Hb A1C 10.5% Insulin therapy: Lantus 24 UI/day

� Hypoglycemia: 3/weeks, no severe hypoglycemia


� Hemodialysis for 4 years

� Blood Group: AB


� Anti HLA antibodies: PRA class I 70%

Case report 2: which transplantation ?

� Pancreas transplantation ?� Islet transplantation ?� Simultaneous pancreas kidney transplantation ?� Simultaneous islet kidney transplantation ?� Kidney transplantation followed by pancreas after kidney ?� Kidney transplantation followed by islet after kidney ?

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Outline

� Procedure:� Pancreas transplantation� Islet graft

� Outcome and beneficial impact:� Pancreas transplantation� Islet graft

� Transplantation strategy

Outline




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Langerhans Islets

ß cell replacement for T1D patients

Pancreas transplantation


T1D patients in ESRD

Pancreas

Simultaneous pancreas and kidney transplantation

Kidney

Pancreas transplant alone

Unstable T1D patientsBrittle diabetes

Pancreas

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SSYYSSTTEEMMIICC

Enteric drainageRoux-en-Y loopLatero-lateral loop

Venous and enteric drainage

Enteric drainageRoux-en-Y loopLatero-lateral loop

Venous and enteric drainage

PPOORRTTAALL

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RecipientT1D patients

Sollinger, Ann Surg, 2009

Pancreas transplantation - a major operation


• Leakage• Hemorrhage• Thrombus of

pancreas…..

High incidence ofpost-operative complications

Early technical failures and graft lossesSimultaneous pancreas and kidney transplantation

Biomedecine agency registry 2016

Graft thrombosis or graft removal because of bleedi ng, anastomotic leaks, pancreatitis, and/or infection.

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Diapo T BerneyIslet graft

ß cell replacement for T1D patients: islet transplantation

T1D patients in ESRD

Islet after kidney transplantation

Kidney

Islet transplant alone

Unstable T1D patientsBrittle diabetes

Islets

Robertson, N Engl J Med, 2004

2-3 Islet preparations per patient

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Rapport ABM 2015

Islet Isolation in France/Geneva

The GRAGIL Network

Geneva

Grenoble

Lyon

BesançonDijon

NancyStrasbourg

Montpellier

Clermont-Ferrand

Berney et al. Curr Opin Organ Transplant 2004; 9: 72.

Kempf et al. Transplantation 2005; 79: 1200.

�1992: Geneva program

�1997: GRAGIL network

�1999: First patient in

France

�272 islet transplantations

�157 patients

Diapo T Berney

Nantes

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Outline




Pancreas and kidney survival in simultaneous pancreas and kidney transplantation

Biomedecine agency registry 2016

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. 2D.

p=0.5075p=0.0008

Buron F et al, Transplantation 2013

Pancreatic re-transplantationPancreas graft survival. Lyon experience

Metabolic follow-up after long-term pancreas graft survival

Dieterle C et al, European Journal of endocrinology 2007

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SPK patient survival by pancreas and kidney graft status

Gruessner AC et al, The review of Diabetic studies, 2016

Impact of simultaneous pancreas and transplantation in Type 1 diabetic patients with ESRD

• Improvement of patient survival (vs Kidney TR or Di alysis)

• Stabilization or improvement of diabetes-related co mplications

•Microvascular• Nephropathy:

Reversal of lesions of diabetic nephropathy on the long termPrevention of diabetic recurrence in kidney graft

•Neuropathy:Improvement of motor and sensory nerve conduction velocity•Retinopathy

stabilization/improvement

• Macrovascular: coronary disease et carotid intima m edia thickness

• Improvement of quality of life

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Reversal of lesions of diabetic nephropathy after pancreas transplantation

Fioretto P,. N Eng J Med 1998; 339: 69.

Before TR 5 years 10 years

Outline




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29%

38%41%

Improvement in Islet transplant outcome

Percentage of insulin independence

(ITA and IAK)

N=659

p=0.02

Barton FB et al Diabetes Care, Vol 35, July 2012

Lablanche S, Diabetes care 2015

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Lablanche S, Diabetes care 2015

Lablanche S et al, The Lancet Diabetes and Endocrinology in press

Assessing Islet transplantation compared to insulin therapy in type 1 diabetes: a randomized parallel study

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Lablanche S et al, The Lancet Diabetes and Endocrinology in press

Assessing Islet transplantation compared to insulin therapy in type 1 diabetes: a randomized parallel study

Improvement of Electrophysiological Neuropathy after Islet Transplantation for Type

1 Diabetes: A 5-year Prospective study

Vantyghem MC et al, Diabetes Care 2014

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Reduced progression of diabetic microvascular complications with Islet cells transplantation compared

with intensive medical therapy

Thompson DM et al, Transplantation 2011

Lehmann R et al, Diabetes Care 2015

Glycemic control in Islet versus Pancreas Transplantation in Type 1 diabetes with ESRD

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Renal function in simultaneous Islet Kidney versus Pancreas Kidney Transplantation in Type 1 diabetes


Simultaneous Islet Kidney versus Pancreas Kidney Transplantation in Type 1 diabetes

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Mittal, Am J transplant, 2014

Antibody mediated rejection in pancreas transplantation

Islet cells are resistant to ABMR

Pouliquen, Am J Transplant, 2017

About a third of islet grafted patients developed DSA

DSA had no significant negative impact on pancreatic islet graft

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Donor heart

Solid organ transplant Islet graft

DSA AllogeneicMHC

Donor isletRecipient

vessel

SyngeneicMHC

Donorvessel

Vascular chimerism

Vascular sequestration of DSAChen C et al, JCI 2018

Pancreas versus islet

Simultaneous

with kidney

After Kidney

Alone

Islet TxPancreas Tx

73%61%

Procedural risk Major procedural risk Minor procedural risk

Immunosuppression

ESRD

Fonctional renal transplant

Life-long Immunosuppression Life-long immunosuppression

Consider SPK Avoid

PAK : glycemic labilitySevere hypoglycemia

IAK : glycemic labilitySevere hypoglycemia

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Outline




Transplantation strategy in Type 1 diabetic patients

� Type 1 diabetic patient and normal renal function (GFR> 50 ml/mn/1.73m2)

� Pancreas or Islet Transplantation ?

� Type 1 diabetic patient and chronic kidney disease (DFG < 50 ml/mn/1.73m2)

� Simultaneous pancreas and kidney transplantation ?

� Simultaneous islet and kidney transplantation ?

� Kidney transplantation followed by pancreas after kidney transplantation ?

� Kidney transplantation followed by islet after kidney transplantation ?

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Pre-emptive kidney transplantation in Type 1 diabetic patients

Pruijm et al, Transplantation 2006, 81:1119

Edmund Huang, Transplantation 2011

•SPK : simultaneous pancreas and kidney transplantation•PALK: pancreas transplantation after living donor kidney transplantation•LDK/no P : living donor kidney transplantation, no pancreas TR•DDK : Deceased donor kidney transplantation, no pancreas TR

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Patients Survival

Similar patients survival in all groupsbut DDK versus PALK (p=0.03)


Kidney Graft Survival


Lower kidney survival for : Preemptive DDK vs preemptive PALK (DDK: 73.0%; log-rank P<0.003)SPK vs preemptive PALK (SPK: 80.2%; log-rank P<0.03)

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Pancreas Graft Survival


Better pancreas graft survivalSPK versus PALK

Key parameters to define transplant strategy in type 1 diabetic patients

� Age (priority < 55 years)

� Sensitization (priority PRA<20%)

� Number of transplantation (priority first transplantation)

� Renal function

� GFR > 50 ml/mn : Islet or pancreas

� GFR <30 ml/m : kidney graft mandatory

� Diabetic control:

� Hb A1c, severe hypoglycemia, microvascular complications

� Surgical risk:

� coronary disease, iliac arterial calcifications, BMI <27 kg/m2

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TREPID group, submitted

durée d’attente

Fon

ctio

n

rén

ale

Dia

bè

teC

ard

iova

scu

lair

e

Imm

un

isa

tio

nD

on

ne

ur

viva

nt

Gre

ffe

50 > eDFG > 30

30 > eDFG > 20

20 > eDFGeDFG > 50

diabète instable

ouinon

0T

état cardiovasculaire compatible avec TP

nonoui

TPS GIS

diabète instable

oui non

oui non

TRP



oui non

TRP


nonoui

TRS

immunisationimportante

non

TRP

oui

donneur vivant

oui

trop longue

non

(TPAR)

(GIAR) TREPID group, submitted

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� Type 1 diabetes


� Hb A1C 8.5% Insulin therapy: Implantable pump

� Hypoglycemia: once a day, no severe hypoglycemia


� GFR : 44 ml/mn/1.73m2 (CKD EPI)

� Blood Group: AB


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durée d’attente

Fon

ctio

n

rén

ale

Dia

bè

teC

ard

iova

scu

lair

e

Imm

un

isa

tio

nD

on

ne

ur

viva

nt

Gre

ffe

50 > eDFG > 30

30 > eDFG > 20

20 > eDFGeDFG > 50

diabète instable

ouinon

0T


nonoui

TPS GIS

diabète instable

oui non

oui non

TRP



oui non

TRP


nonoui

TRS

immunisationimportante

non

TRP

oui

donneur vivant

oui

trop longue

non

(TPAR)

(GIAR) TREPID group, submitted

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� Type 1 diabetes

� BMI 22 kg/M2


� Hb A1C 10.5% Insulin therapy: Lantus 24 UI/day

� Hypoglycemia: 3/weeks, no severe hypoglycemia


� Hemodialysis for 4 years

� Blood Group: AB


� Anti HLA antibodies: PRA class I: 70%

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PRA > 70%No priority

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Kidney TransplantationLiving donor > Dcd donor


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Acknowledgments� Transplantation, nephrology and clinical immunology : � M Brunet F Buron C Levi S Daoud O Thaunat R Cahen, C Pouteil-Noble,

Antoine Sicard, A Koenig, C Fournie� Diabetology :� C Thivolet - M Laville- S Reffet� Anesthesiology/Intensive care unit :� T Rimmelle- A Bertin- C Jadaud- G Marcotte� Surgical team

� L Badet� X Martin� R Codas� H Fassi Fehri� M Colombel� S Crouzet

� Gragil network : � T Berney, PY Benhamou, L Kessler….

� TREPID group� Esposito AL, Badet L, Gragil, Paris, Lille’s groups

Thank you

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