Pancreas-Transplantasjon i Norge Høy komplikasjonsrate men i vellykkede $lfeller er det meget $lfredss$llende da pasienten over naaen blir: - Fri fra Insulin - Fri fra Dialyse (SPK) Svær økning i antall Pancreas-Tx (PTx) unørt ila de siste år - Og en meget høy andel solitær-ptx (dvs kun pancreas/ikke nyre) Ole Øyen Oslo University Hospital Rikshospitalet NORWAY Sec$on for Transplant Surgery
PANCREAS-Tx Anatomi - Teknisk vanskelig lokalisert - De ønskelige Insulin- produserende β-cellene utgjør kun 1-2 % av organet >95 % er exocrint vev
PANCREAS-Tx: Problemer Kirurgi Vanskelig, skjørt Tx-organ Potent enzym-pakke Tynn, skjør kapsel Tilgang: På bakre bukvegg Sammenvokst med duodenum Kompleks kar-anatomi Atraumatisk teknikk essensiell Utfordrende hemostase Antikoagulasjon Høy thrombose-risiko Overdimesjonerte sentrale kar Delikat balanse mellom blødning og thrombose Immunologi; Avstøtning Høygradig immunsuppresjon nødvendig Høy risiko for komplikasjoner - Mange reoperasjoner Infeksjoner / Cancer
PANCREAS-Tx: Typer/Indikasjoner Simultan Pancreas- + Nyre-Tx (SPK) - Diabetes mellitus type 1 pas m/ nyresvikt < 50-60 år - Bedre resultatermed SPK vs Sol-PTx Solitær Pancreas-Tx (Sol-PTx) Selekterte ikke-uremiske DM pas (BriAle DM1 / Unawareness) Pancreas-Tx alene (PTA) Pancreas-Tx eaer $dligere Nyre-Tx (PAK) og/eller $dligere Øycelle-Tx (PAI)
Antall/type av PTx i Norge 1983-2015 45 40 SPK PAK/PAI PTA 35 30 25 20 Sol- PTx 15 10 5 0 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015
Pancreas-Tx per mill. popula$on - 2014 Sec$on for Transplant Surgery
PANCREAS-Tx in Norway Surgical tecnique: Explantation The handling of pancreas during removal is demanding and decisive - Atraumatic technique is essential ( no touch ) LigaSure Technically a quantum leap Vessels - Preferably coeliac trunk and superior mesenteric art. on common aortic segment - Preferably long portal vein - Ligation/sealing of all other vessels
Surgical technique: Transplanta$on Simultaneous Pancreas + Kidney Tx (SPK) Entero-anastomosis: Tx-duodenum Jejunum Tx-Kidney anastomoses: External Iliac Vein/Artery Urinary bladder Systemic venous anastomosis: Portal Vein Vena Cava Arterial anastomosis: Coeliac Trunk + Sup Mes Art Common Iliac Art dxt
Pancreas-Tx in Norway: HISTORY Era I: 1983-1988 Era III: 1997-2012 Era II: 1988-1997 Era IV: 2012-2016
Pancreas-Tx in Norway: History IMMUNOSUPPRESSION 1983 CyA + Aza + CS 1997 CyA + MMF + CS 2000 Tacrolimus + MMF + CS 2003 Tac + MMF + CS + ATG 1 dose 2005 Tac + MMF + CS + ATG 1-2 doses* 2010 Tac + MMF + CS + ATG 2-3 doses* 2011 Solitary PTx: T-cell suppression for 10 d 2012 All PTx: T-cell suppression for 10 d MMF reduced *guided by daily T-cell number
Pancreas-Tx in Norway: History ANTICOAGULATION 1983-2012 Macrodex (Dextran) 500 ml Day 0 + 1 + 3 + 5 Acetyl Salicylic Acid (ASA) from day 6 2012- Fragmin SPK 5000-7500ie un$l day 7 5000ie un$l 6wks biopsy ASA from day 7
Pancreas-Tx in Norway: History Other changes Scheduled biopsies 2010 Kidney 6 wks and 1 year 2010 Duodenal segment 10 wks 2012 Duodenal segment and pancreas wks 3, 6 and 52. (10wks abandoned) 2015 Percutaneous P-biopsy wks 6 (Study Protocol) An$fungal prophylaxis and exocrine suppression 2012- Diflucan abandoned 2012- Sandosta$n abandoned Ulcus prophylaxis 2012 - Somac 40 mg x 2 (first two weeks, then 40mg x1)
13 Pitfalls and challenges Streng seleksjon av egnede donorer Streng seleksjon på donorsiden medfører streng seleksjon på recipientsiden PancreasTX er ledsaget av høy komplikasjonsrate sammenlignet med nyretx Tromboser, Blødninger, Eksokrin lekkasje, Infeksjon, Ileus Det er økt rejeksjonsfare og grafttap som følge av rejeksjon sammenlignet med andre organtransplantasjoner
14 Donorseleksjon Alder <55, helst under 45. I praksis ingen nedre aldersgrense Normal HbA1c Ingen historie på pankreatitt/sykdom i pancreas BMI <30 Komorbiditet bør unngås, spesielt uttalt aterosklerose og nyresvikt Endelig godkjenning av graftet gjøres peroperativt
15 Hvorfor så streng seleksjon på donor og recipientsiden? Komplikasjoner/reoperasjoner Graftsurvival Pasientsurvival
UNordringer Short term: KIR. KOMPLIKASJONER Long term: REJEKSJONER
FUTURE STUDIES Ques$ons to be adressed Prospec$ve PTx study started in Oct. 2013 The value of endoscopic/scheduled biopsies?? Duodenal segment biopsies? Pancreas biopsies? Reasons for poorer Solitary PTx results?? Impeded rejec$on monitoring due to lack of reporter-kidney? Immunologically protec$on due to TX-kidney? S$ll to weak immunosuppression? Non-invasive rejec$on monitoring? C-pep:de - CRP - Amylase - Lipase? Advanced immunologic markers?
Preliminary data ongoing PTx-study 09-2013 -> N = 67 (per 20.01.16): 35 S-PTx, 32 SPK PS 66/67 = 99% GS 61/67 =91% Grax loss 2 thrombosis, 3 rejec$on (PTA, AMR), 1 bleeding Thrombosis rate 5/67 cases (7%) 2 Graxectomy. 3 underwent successful perc. thrombectomy Reopera$on rate 17/67 (25%) Rejec$on rate is higher in PTA AMR predicts very poor outcome in PTA Sec$on for Transplant Surgery
Lindahl et al. Diabetologia 2013 Sec$on for Transplant Surgery
PTx in Norway: Results I (Lindahl et al. 2013) Sec$on for Transplant Surgery
PTx in Norway: Results II (Lindahl et al. 2013)
PTx in Norway: Risk factors for death (Lindahl et al. 2013) Cox regression analysis of risk factors for patient death. Univariate analysis Multivariate analysis Model 1 Multivariate analysis Model 2 HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value Recipient age 1.03 1.02-1.04 <0.001 1.03 1.02-1.04 <0.001 1.03 1.02-1.04 <0.001 Recipient gender Treatment LDK (n=171) SPK (n=222) DDK (n=237) 1.06 0.83-1.34 0.65 0.68 1.82 Reference 0.51-0.91 1.39-2.37 0.010 <0.001 0.70 1.29 Reference 0.52-0.95 0.96-1.75 0.02 0.094 0.84 1.41 0.60-1.18 1.04-1.93 Time on dialysis 1.0006 1.0002-1.0009 0.001 1.001 1.000-1.001 0.001 1.001 1.000-1.001 0.001 Transplant era 1983-1999 (n=304) 2000-2010 (n=326) 0.32 0.029 0.57 0.43-0.77 <0.001 0.41 0.30-0.56 <0.001 0.40 0.30-0.55 <0.001 Donor age 1.01 1.01-1.02 <0.001 1.01 1.00-1.02 0.018
PTx in Norway: Conclusions I (Lindahl et al. 2013) Recipients receiving SPK have superior pa$ent survival compared to both LDK and DDK Significantly improved grax and pa$ent survival during the last decade Significant effect on pa$ent death by: Transplant era Time on dialysis Donor age Recipient age
Horneland et al., Am J Transpl, 2015
Horneland et al., Am J Transpl, 2015 DD vs DJ - inital experience # (%) / Mean (range) / Mean ± SD PTx-DD Sep 2012 Sep 2013 n=40 PTx-DJ (Control) Feb 2011 Sep 2012 n=40 p t-test/ Fisher exact Reoperations (# patients) - Bleeding/Thrombosis/Exocrine Leakage / Kidney related/other 19 (47,5%) 8 / 4 / 0 / 2 / 6 12 (30%) 6 / 2 / 2 / 0 / 2 0.168 Pancreas venous thrombosis rate - Graft loss due to v. thrombosis 9 (22,5%) 5 (12,5%) 2 (5%) 2 (5%) 0.048* 0.432 Rejection rate; biopsy-verif. (# pts) - Total # of rejections treated 9 (22,5%) 14 10 (25%) 11 1.000 Pancreas Graft loss 8 (20%) 5 (12,5%) 0.546 Kidney Graft loss (SPK) 1 (2,5%) 1 (3,3%) 1.000 Patient death 1 (2,5%) 3 (7,5%) 0.615
Grax Survival Singel vs Kombinert PTX Sec$on for Transplant Surgery
Cox regression Dependent var.: Pancreas graft loss Horneland et al., Am J Transpl, 2015 Risc factor analysis Independent covar. w/ statistical significance at p < 0.15 included p Univariate analysis Hazard Ratio (95% CI) p Multivariate analysis Hazard Ratio (95% CI) Time on waiting list 0.007* 1.00 (1.00-1.00) 0.493 1.00 (1.00-.1.00) HLA -A+B mismatches - DR mismatches 0.038* 0.549 0.51 (0.27-0.96) 0.76 (0.31-1.87) 0.323 0.69 (0.34-1.43) - Patient death Recipient age 0.009* 1.21 (1.05-1.41) 0.066* 1.24 (0.99-1.56) Binary logistic Regression Dependent var.: Reoperation Per patient; (one or more reop.) Time on waiting list 0.008* 1.00 (1.00-1.00) 0.906 1.00 (1.00-1.01) HLA -A+B mismatches - DR mismatches Independent variables w/ statistical significance at p < 0.15 included 0.038* 0.211 p 0.33 (0.11-0.94) 0.36 (0.07-1.79) Univariate analysis Odds Ratio (95% CI) 0.437 - p 0.51 (0.09-2.79) - Multivariate analysis Odds Ratio (95% CI) Recipient BMI 0.040* 1.17 (1.01-1.36) 0.039* 1.30 (1.01-1.67) Donor age: - Continous var. - <50 vs > 50 - <45 vs > 45 - <40 vs > 40 0.028* 0.035* 0.005* 0.042* 1.04 (1.00-1.08) 3.41 (1.09-10.66) 4.16 (1.55-11.19) 2.61 (1.03-6.57) 0.021* 1.08 (1.01-1.14)
The duodenoduodenostomy: Sten$ng the pancrea$c duct
CONCLUSIONS II (Horneland et al.) A huge increase in PTx during recent years A very high rate of Sol-PTx Releasing on donor criteria (age etc) is dangerous S$ll a high rate of reopera$ons (20-40%) A high rate of thrombosis Solitary PTx results are sbll poorer than SPK! Duodeno-duodenostomi offers improved access for biopsies and ductal sten$ng Value of scheduled EUS biopsies s$ll not proven
Øycelle-Tx?? FRAMTIDEN?? FortsaA få Insulin-frie eaer 3-5 år?? FortsaA avhengige av høygradig immunsuppresjon Andre hormoner/mediatorer Mekaniske, glucose-sensible Insulin-pumper? Trenger ingen immunsuppresjon Stamceller? Autolog transplantasjon Trenger ingen immunsuppresjon!