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30/01/2019
1
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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Case report 2� Female 27 years old
� Type 1 diabetes
� Diabetes duration: 18 years
� Hb A1C 10.5% Insulin therapy: Lantus 24 UI/day
� Hypoglycemia: 3/weeks, no severe hypoglycemia
� Diabetes complication: neuropathy, retinopathy, nephropathy
� Hemodialysis for 4 years
� Blood Group: AB
� No evidence for macroangiopathy
� 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
� Procedure:� Pancreas transplantation� Islet graft
� Outcome and beneficial impact:� Pancreas transplantation� Islet graft
� Transplantation strategy
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Langerhans Islets
ß cell replacement for T1D patients
Pancreas transplantation
ß cell replacement for T1D patients
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
ß cell replacement for T1D patients
• 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
� Procedure:� Pancreas transplantation� Islet graft
� Outcome and beneficial impact:� Pancreas transplantation� Islet graft
� Transplantation strategy
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
� Procedure:� Pancreas transplantation� Islet graft
� Outcome and beneficial impact:� Pancreas transplantation� Islet graft
� Transplantation strategy
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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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Lehmann R et al, Diabetes Care 2015
Renal function in simultaneous Islet Kidney versus Pancreas Kidney Transplantation in Type 1 diabetes
Lehmann R et al, Diabetes Care 2015
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
� Procedure:� Pancreas transplantation� Islet graft
� Outcome and beneficial impact:� Pancreas transplantation� Islet graft
� Transplantation strategy
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)
Edmund Huang, Transplantation 2011
Kidney Graft Survival
Edmund Huang, Transplantation 2011
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
Edmund Huang, Transplantation 2011
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
état cardiovasculaire compatible avec TP
état cardiovasculaire compatible avec TP
oui non
TRP
état cardiovasculaire compatible avec TP
nonoui
TRS
immunisationimportante
non
TRP
oui
donneur vivant
oui
trop longue
non
(TPAR)
(GIAR) TREPID group, submitted
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TREPID group, submitted
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
30/01/2019
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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
état cardiovasculaire compatible avec TP
nonoui
TPS GIS
diabète instable
oui non
oui non
TRP
état cardiovasculaire compatible avec TP
état cardiovasculaire compatible avec TP
oui non
TRP
état cardiovasculaire compatible avec TP
nonoui
TRS
immunisationimportante
non
TRP
oui
donneur vivant
oui
trop longue
non
(TPAR)
(GIAR) TREPID group, submitted
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Case report 2� Female 27 years old
� Type 1 diabetes
� BMI 22 kg/M2
� Diabetes duration: 18 years
� Hb A1C 10.5% Insulin therapy: Lantus 24 UI/day
� Hypoglycemia: 3/weeks, no severe hypoglycemia
� Diabetes complication: neuropathy, retinopathy, nephropathy
� Hemodialysis for 4 years
� Blood Group: AB
� No evidence for macroangiopathy
� Anti HLA antibodies: PRA class I: 70%
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PRA > 70%No priority
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Kidney TransplantationLiving donor > Dcd donor
TREPID group, submitted
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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