Pancreas Transplantation: A Daring Concept 17 December 1966

Transcription

1 Pancreas Transplantation Pancreas Transplantation: A Daring Concept 17 December 1966 Rutger J. Ploeg, MD PhD Abdominal & Transplant Surgery University Medical Centre Groningen The Netherlands Diabetes Mellitus Type I or II Risk of Nephropathy Natural History Type I Diabetic Nephropathy Clinical Stages Defined by Mogensen Late onset GFR (ml/min) 15 5 I II III IV V Albuminuria (mg/day) Haslacherl, NDT Intensive Insulin Treatment How Intensive Do We Want It? Pancreas Transplantation: An Entity with Different Treatment Options SPK : Simultaneous Pancreas and Kidney transplantation PAK : Pancreas After Kidney Pancreas transplantation PTA: Pancreas Transplantation Alone DCCT, NEJM

2 IPTR: Pancreas Transplantation Worldwide Numbers & Type DM Type I Patients in Eurotransplant Waiting List & Transplantation Waiting list SPK PTA + PAK Islets Eurotransplant Annual Report 23 Pancreas Transplant Centres The Netherlands Bridging Graft Viability from Donor to Recipient: Identify Risk Factors Recipient Age & condition Immunological status Posttx management Immunosuppression Preservation Cold storage Composition solution Preservation time Reperfusion injury Donor Age & condition Cardiac arrest Hypotension Management Nutritional status BMI Brain death Successful Transplantation Starts in the Donor Basic Concept in Organ Preservation Hypothermia -4 C Wash-out & removal blood Rapid cooling surface and intravascular equilibration Ischemic injury Suspension in the cold with metabolism No O 2 - no nutrients 2

3 Final Inspection Donor Pancreas Back-Bench Procedure Pancreatic Graft Pancreas & Kidney Transplantation Exocrine Drainage: Bladder or Enteric? Pancreas Transplantation with Bladder Drainage Disadvantage Metabolic acidosis & bicarbonate loss Inflammation & persistent lesion lower urinary tract due to urinary amylase excretion More infections urinary tract Advantage Urinary amylase monitoring Safe technique, low chance abdominal complication Enteric conversion is possible if necessary Pancreas Transplantation with Enteric Drainage Pancreas Transplantation with Systemic or Portal Venous Drainage Disadvantage If leakage of bowel content relaparotomy and abdominal sepsis No urinary amylase monitoring Advantage More physiological than bladder connection No bicarbonate loss by urinary tract Systemic venous drainage (SVD) is widely used, systemic hyperinsulinemia Portal venous drainage (PVD ) is more physiological, increased chance thrombosis No superiority in graft & patient survival or effect on long term diabetes complications of either technique 3

4 Pancreas Transplantation Causes of Graft Failure: An Unhappy Start Better Preservation with Less Ischemic Injury & Pancreas Thrombosis 21% 9% Thrombosis Death with function Chronic tx dysfunction 1% Pancreatitis Acute rejection 3% 9% 16% 32% Infection PNF University of Wisconsin Solution Stratta et al, Clin Transplantation 1999 Belzer & Southard, 1986 Why was the UW Solution invented: Pancreas Transplantation Early Complications What has happened since then? Still reperfusion edema with pancreatic sweating Occasionally graft pancreatitis in fatty grafts Significantly reduced incidence of acute rejection Lower incidence of infectious complications The Real Reason Comfortable Pancreas Preservation Times! Rare: Leakage from duodenal segment Rare: Thrombosis due to low flow organ status Diabetes Mellitus Type I Renal Replacement Therapy & Patient Survival Cumulative Survival (%) 4 Dialysis Cumulative survival (%) 4 SPK Tx Kidney Tx after start Renal Replacement Therapy after start Renal Replacement Therapy Smets et al, Lancet

5 Diabetes Mellitus Type I with ESRD Patient Survival Groningen Incidence Acute Rejection before 2 Single Centre: Recipient & Donor Age <5 y At Risk (%) Kidney SPK Acute Rejection (%) SPK Tx 75 5 Kidney Tx (non-diabetics) 25 SPK vs KTx: p= Time (days) Acute Rejection in Kidney Transplantation First Cadaveric Grafts (P-CsA) Acute Rejection after SPK Modern immunosuppressive drugs Multivariate RR (95%-CI) p-value 1. Cold Ischemic Time (h).99 ( ).2 Delayed Function 1.24 ( ).1 Recipient Age (< 5 yr) 1.34 ( ) <.5 Donor Age ( 5 yr) 1.53 ( ) <.5 Cumulative Incidence of AR % HLA-DR mismatch ( 1) 2.28 ( ) < Days after Transplantation J Am Soc Nephrol 21 Pancreas Transplantation Most Common Immunosuppressive Regimen SPK Results in Leiden & Groningen 1 yr Patient & Graft Survival ( ) Induction Maintenance ATG 9 mg/kg bw (rabbit) or Basiliximab/Dacluzimab Prednisolone 2 mg MMF 2 x 1 g Cyclosporine or Tacrolimus Prednisolone 1 mg MMF 2 x 1 gram. Patient Kidney Pancreas Non USA N = % 91% 85% Leiden N=95 98% 97% 91% Groningen N=38 98% 98% 87% 5

6 Simultaneous Pancreas Kidney Transplants Long-term Outcome Simultaneous Pancreas Kidney Transplantation Graft Function Kidney 9 Modern (n=95) 9 6 Months 12 Months 7 Classic (n=83) 7 5 p<.1 5 p= HbA1c 5.4 ± ±.6 Pancreas GFR 54 ± 1 55 ± 11 5 p=.5 5 p= Censored Uncensored Who is Eligible for SPK Transplantation? Effect of SPK on Diabetic Complications Type 1 DM & C-peptide negative ESRD is present & CrCl < 15 ml/min Acceptable vascular status, no major amputations CAG prior to tx < 1 year Age preferably < year Glucose control Cardiovascular Retinopathy Nephropathy Neuropathy Quality of Life? SPK and Glucose Control Cardiovascular Mortality in Type I DM Rapid intra-operative normalization of glucose is the rule 2 18,1 17,6 In case of systemic venous drainage fasting insuline 2-3 x higher than control % ,8 5 Dialysis Kidney Tx SPK Tx Secchi A et al. Lancet

7 Initially sometimes shortime worsening Beneficial effects after 36 m post-transplant, less need for laser treatment, fewer vitreous hemorrage. Incremental advantage of SPK compared to KTA Advanced diabetic retinopathy may not benefit SPK and Retinopathy % % % 4% 2% % SPK KTA Improved Stable Progressed NEJM 1998 SPK and Diabetic Nephropathy in Native Kidneys Konigsrainer et al. Diabetologia 1991; Scheider et al. Diabetologia 1994 SPK and Nephropathy SPK and Neuropathy Preservation glomerular basement membrane thickness, mean glomerular volume, and mesangial volume fraction Bilous et al. NEJM 1989 Basement membrane thickness within 2 SD of normal in 92% of SPK vs 35% of KTA patients after up to 6 y Wilczek et al. Transplantation 1995 Autonomic neuropathy improved, however only after a long time. Nusser et al. Diabetologia 1991 Gastric emptying improved Gaber et al. Transplant Proc 1994 Peripheral sensory-motor neuropathy improved after 2 years Muller-Felber et al. Diabetes 1993 Motor and sensory nerve conduction velocity progressively improved over 8 years Solders et al. Transplant Proc 1995 SPK and Quality of Life Pancreas Transplantation Alone (PTA) Improved global quality of life Less anxiety & improved sense of physical well-being (SPK) No dietary restrictions (SPK) Improvements in physical limitations (SPK) Reintegration-to-normal-living index (SPK) Indication: Severe hypoglycemic unawareness Preference: Bladder drainage to monitor amylase More complications, PTLD, deteroriation native renal function 4 performed, all patients alive, but all patients require insuline again, longest graft survival 6 y Caution is advised when performing this type JAMA 23 Reviewed in Landgraf et al. Diabetologia

8 Pancreas Transplant Alone (PTA) Graft Survival by Era % n 1Yr Surv % % % % Months Posttransplant Transplant Options for Type 1 DM with ESRD Pancreas or Islet Transplantation? Pancreas Islets > Edmonton Deceased Donor Kidney Tx : Poor option, however better than dialysis Living Donor Kidney Tx : Comparable to SPK, less glucose control, better kidney survival, equal patient survival SPK Tx: More or Equal to LD Ktx : when age <5 = Primary Option, especially in the absence of living donor LD or HB Ktx + PAK: Results less than with SPK Insuline-free after 1 year 85-9 % 2-25 % Number of donor organs 1 3 Number of transplants Procedure Major surgery Less invasive Immunosupression Lifelong Lifelong Organ failure Allo-immunity Allo + Auto Insuline-free after 5 yr 1 yr 74 % 71 %?? Are we running in the right direction? I don t know, but we are getting somewhere 8

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10 5 Different Strategies of Treatment in Type 1 DM with ESRD Gain in Life Expectancy Treatment Option Dialysis 7.8 Cadaveric kidney tx 11.4 SPK tx 15.7 PAK tx 17.2 Living donor kidney tx 18.3 Knoll & Nichol, Am Soc Nephrology 23 Cell Swelling Effective Wash-out prior to Organ Preservation Experiment: Interaction Starch & Blood? Moriaru, van der Plaats, t Hart Bright Field Microscopy: magnification 5 x Hypothermia - 4 C From donor organs: Removal of blood Rapid cooling surface and Intravascular equilibration Control RBC suspended in autologus plasma HES 45kDa induced RBC polymorph clusters HES 13kDa induced linear RBC rouleaux UW induced branched RBC rouleaux networks Absence of RBC aggregation after treatment with HES-free UW Improving Concepts in Organ Preservation To Develop a Preservation Solution Hypothermia - 4 C Removal blood Rapid cooling Suspension in the cold Ischemic injury Adequate wash-out is crucial Counteract 4 classic unwanted effects of hypothermia Cell swelling Impaired energy metabolism Acidosis Precursors of ROS: reperfusion injury Choice components is crucial Solution effect! 1

11 Achieve Optimal Physical Environment Intensive Insulin Treatment Created by agents in the solution Progression of Retinopathy Severe hypoglycemia Cell swelling and buffering Osmotic pressure = Impermeants Saccharides glucose, mannitol, sucrose, raffinose Anions lactobionate, PO 4, citrate Electrolytes Na, K, histidine Oncotic pressure HES, PEG, dextran H + - buffers PO 4, histidine DCCT, NEJM 1993 Diabetic Nephropathy Clinical stages defined by albuminuria Simultaneous Pancreas Kidney Transplants Improved Graft Survival over Time Stage Albuminuria (mg/day) GFR Renal lesions I Hyperfiltration / reversible 1..8 Kidney ATG-NEO- MMF NEO-AZA 1..8 Pancreas II Subclinical < 3 /= reversible III Incipient > 3 = reversible Survival rate.6 SIM-AZA Survival rate.6 IV Overt > 3 =/ progressive irreversible V End-stage irreversible post-transplant 5 1 post-transplant De Feijter et al. Patient Survival for UNOS/IPTR 11

12 Acute Rejection Episodes after SPK Influx of Mononuclear Cells SPK and Vasculopathy, CAD at Time of Transplant Evaluation Pretransplant coronary angiography < 5% Age Smoking (%) as a diabetic Time to transplant (months) 5-74% 75% n=93 n=46 n=59 35 ± 7 4 ± 9 42 ± ± 6 25 ± 8 26 ± 7 9 ± 9 8 ± 8 11 ± 9 59 Follow-up at 36 months 1 vascular event 11% 3% 55% (Amp, MI, CVA) - amputation 9% 23% - myocardial infarction 1% 11% 4% 18% (despite revascularization) Boonstra et al Why was the UW Solution invented: Manske et al, Am J Kidney Dis 1997 Tubular & Glomerular Remodelling Extracellular Matrix after PTA Cortical Interstitial Volume Fraction Fractional Volume ATs 5 years 1 years The Real Reason: Comfortable Long Preservation Times! Fioretti et al, Kidney Int 26 12