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
Disclosure Advisory Boards : Novartis, Chiesi, Astellas, Sanofi Symposium: BMS, Sanofi, Astellas, Chiesi, Sandoz, Roche, IGL Research grants: Novartis, Astellas, Chiesi
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/1.73m 2 (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?
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?
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
ß cell replacement for T1D patients Pancreas transplantation Langerhans Islets
ß cell replacement for T1D patients Simultaneous pancreas and kidney transplantation Pancreas transplant alone Pancreas Kidney Pancreas T1D patients in ESRD Unstable T1D patients Brittle diabetes
Venous and enteric drainage S Y S T E M I C Enteric drainage Roux-en-Y loop Latero-lateral loop
Venous and enteric drainage P O R T A L Enteric drainage Roux-en-Y loop Latero-lateral loop
ß cell replacement for T1D patients Pancreas transplantation - a major operation High incidence of post-operative complications Recipient T1D patients Leakage Hemorrhage Thrombus of pancreas.. Sollinger, Ann Surg, 2009
Early technical failures and graft losses Simultaneous pancreas and kidney transplantation Graft thrombosis or graft removal because of bleeding, anastomotic leaks, pancreatitis, and/or infection. Biomedecine agency registry 2016
Islet graft Diapo T Berney
ß cell replacement for T1D patients: islet transplantation Islet transplant alone Islet after kidney transplantation Islets Kidney 2-3 Islet preparations per patient Unstable T1D patients Brittle diabetes T1D patients in ESRD Robertson, N Engl J Med, 2004
Islet Isolation in France/Geneva Rapport ABM 2015
The GRAGIL Network 1992: Geneva program Nantes Nancy Dijon Strasbourg Besançon 1997: GRAGIL network 1999: First patient in France Clermont-Ferrand Lyon Geneva Grenoble 272 islet transplantations 157 patients Montpellier Berney et al. Curr Opin Organ Transplant 2004; 9: 72. Kempf et al. Transplantation 2005; 79: 1200. Diapo T Berney
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
Pancreatic re-transplantation Pancreas graft survival. Lyon experience. 2D. p=0.0008 p=0.5075 Buron F et al, Transplantation 2013
Metabolic follow-up after long-term pancreas graft survival Dieterle C et al, European Journal of endocrinology 2007
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 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
Reversal of lesions of diabetic nephropathy after pancreas transplantation Before TR 5 years 10 years Fioretto P,. N Eng J Med 1998; 339: 69.
Outline Procedure: Pancreas transplantation Islet graft Outcome and beneficial impact: Pancreas transplantation Islet graft Transplantation strategy
Barton FB et al Diabetes Care, Vol 35, July 2012 Improvement in Islet transplant outcome 29 % 38% 41 % N=659 p=0.02 Percentage of insulin independence (ITA and IAK)
Lablanche S, Diabetes care 2015
Lablanche S, Diabetes care 2015
Assessing Islet transplantation compared to insulin therapy in type 1 diabetes: a randomized parallel study 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 Lablanche S et al, The Lancet Diabetes and Endocrinology in press
Improvement of Electrophysiological Neuropathy after Islet Transplantation for Type 1 Diabetes: A 5-year Prospective study Vantyghem MC et al, Diabetes Care 2014
Reduced progression of diabetic microvascular complications with Islet cells transplantation compared with intensive medical therapy Thompson DM et al, Transplantation 2011
Glycemic control in Islet versus Pancreas Transplantation in Type 1 diabetes with ESRD 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 Lehmann R et al, Diabetes Care 2015
Antibody mediated rejection in pancreas transplantation Mittal, Am J transplant, 2014
Islet cells are resistant to ABMR About a third of islet grafted patients developed DSA DSA had no significant negative impact on pancreatic islet graft Pouliquen, Am J Transplant, 2017
Solid organ transplant Vascular chimerism Islet graft Donor heart Donor vessel Donor islet Recipient vessel DSA Allogeneic MHC Syngeneic MHC Vascular sequestration of DSA Chen C et al, JCI 2018
Pancreas versus islet Simultaneous with kidney After Kidney Pancreas Tx Islet Tx Alone 73% 61% Procedural risk Major procedural risk Minor procedural risk Immunosuppression Life-long Immunosuppression Life-long immunosuppression ESRD Fonctional renal transplant Consider SPK PAK : glycemic lability Severe hypoglycemia Avoid IAK : glycemic lability Severe hypoglycemia
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?
Pre-emptive kidney transplantation in Type 1 diabetic patients Pruijm et al, Transplantation 2006, 81:1119
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 Edmund Huang, Transplantation 2011
Patients Survival Similar patients survival in all groups but DDK versus PALK (p=0.03) Edmund Huang, Transplantation 2011
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) Edmund Huang, Transplantation 2011
Pancreas Graft Survival Better pancreas graft survival SPK versus PALK Edmund Huang, Transplantation 2011
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
TREPID group, submitted
Greffe Donneur vivant Immunisation Cardiovasculair e Diabète Fonction rénale edfg > 50 50 > edfg > 30 > edfg > 20 > edfg 30 20 diabète instable non oui diabète instable oui non état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP oui non oui non oui non oui non immunisation importante non oui donneur vivant non oui 0T durée d attente TPS GIS TRP TRP TRP TR trop longue (TPAR (GIAR) TREPID group, submitted S )
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/1.73m 2 (CKD EPI) Blood Group: AB No evidence for macroangiopathy
Greffe Donneur vivant Immunisation Cardiovasculair e Diabète Fonction rénale edfg > 50 50 > edfg > 30 > edfg > 20 > edfg 30 20 diabète instable non oui diabète instable oui non état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP état cardiovasculaire compatible avec TP oui non oui non oui non oui non immunisation importante non oui donneur vivant non oui 0T durée d attente TPS GIS TRP TRP TRP TR trop longue (TPAR (GIAR) TREPID group, submitted S )
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%
PRA > 70% No priority
Kidney Transplantation Living donor > Dcd donor
TREPID group, submitted
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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