stratégie de transplantation chez le patient diabétique de...
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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 Clinique
Hôpital Edouard Herriot – LYON
Inserm U 1111
Actualités Néphrologiques Jean Hamburger
Hôpital Necker
23 avril 2018
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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
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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%
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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
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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
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ß cell replacement for T1D patients
T1D patients in ESRD
Pancreas
Simultaneous
pancreas and kidney transplantation
Kidney
Pancreas transplant alone
Unstable T1D patients
Brittle diabetes
Pancreas
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S
Y
S
T
E
M
I
C
Enteric drainage Roux-en-Y loop
Latero-lateral loop
Venous and enteric drainage
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Enteric drainage Roux-en-Y loop
Latero-lateral loop
Venous and enteric drainage
P
O
R
T
A
L
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Recipient
T1D patients
Sollinger, Ann Surg, 2009
Pancreas transplantation - a major operation
ß cell replacement for T1D patients
• Leakage
• Hemorrhage
• Thrombus of
pancreas…..
High incidence of post-operative complications
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Early technical failures and graft losses
Simultaneous pancreas and kidney transplantation
Biomedecine agency registry 2016
Graft thrombosis or graft removal because of bleeding, anastomotic leaks,
pancreatitis, and/or infection.
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Diapo T Berney Islet graft
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ß cell replacement for T1D patients: islet transplantation
T1D patients in ESRD
Islet after kidney transplantation
Kidney
Islet transplant alone
Unstable T1D patients
Brittle 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
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The GRAGIL Network
Geneva
Grenoble
Lyon
Besançon Dijon
Nancy Strasbourg
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
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Pancreas and kidney survival in simultaneous
pancreas and kidney transplantation
Biomedecine agency registry 2016
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. 2D.
p=0.5075 p=0.0008
Buron F et al, Transplantation 2013
Pancreatic re-transplantation
Pancreas graft survival. Lyon experience
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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
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Impact of simultaneous pancreas and transplantation
in Type 1 diabetic patients with ESRD
• Improvement of patient survival (vs Kidney TR or Dialysis)
• Stabilization or improvement of diabetes-related complications
•Microvascular
• Nephropathy: Reversal of lesions of diabetic nephropathy on the long term
Prevention of diabetic recurrence in kidney graft
•Neuropathy: Improvement of motor and sensory nerve conduction velocity
•Retinopathy stabilization/improvement
• Macrovascular: coronary disease et carotid intima media 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
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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
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Lablanche S, Diabetes care 2015
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Lablanche S, Diabetes care 2015
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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
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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
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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
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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
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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
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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 Allogeneic
MHC
Donor islet Recipient
vessel
Syngeneic
MHC
Donor
vessel
Vascular chimerism
Vascular sequestration of DSA
Chen C et al, JCI 2018
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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 lability
Severe hypoglycemia IAK : glycemic lability
Severe hypoglycemia
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Outline
Procedure:
Pancreas transplantation
Islet graft
Outcome and beneficial impact:
Pancreas transplantation
Islet graft
Transplantation strategy
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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
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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 groups
but DDK versus PALK (p=0.03)
Edmund Huang, Transplantation 2011
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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 survival
SPK versus PALK
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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
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durée d’attente
Fonct
ion
rénale
D
iabète
Card
iova
scula
ire
Imm
unis
ation
Donneur
viv
ant
Gre
ffe
50 > eDFG > 30
30 > eDFG > 20
20 > eDFG eDFG > 50
diabète instable
oui non
0T
état cardiovasculaire compatible avec TP
non oui
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
non oui
TRS
immunisation
importante
non
TRP
oui
donneur vivant
oui
trop longue
non
(TPAR)
(GIAR) TREPID group, submitted
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TREPID group, submitted
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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
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durée d’attente
Fonct
ion
rénale
D
iabète
Card
iova
scula
ire
Imm
unis
ation
Donneur
viv
ant
Gre
ffe
50 > eDFG > 30
30 > eDFG > 20
20 > eDFG eDFG > 50
diabète instable
oui non
0T
état cardiovasculaire compatible avec TP
non oui
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
non oui
TRS
immunisation
importante
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 Transplantation
Living donor > Dcd donor
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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
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Thank you