Pancreas-Transplantasjon i Norge

Transkript

1 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

2 PANCREAS-Tx Anatomi - Teknisk vanskelig lokalisert - De ønskelige Insulin- produserende β-cellene utgjør kun 1-2 % av organet >95 % er exocrint vev

3 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

4 PANCREAS-Tx: Typer/Indikasjoner Simultan Pancreas- + Nyre-Tx (SPK) - Diabetes mellitus type 1 pas m/ nyresvikt < 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)

5 Antall/type av PTx i Norge SPK PAK/PAI PTA Sol- PTx

6 Pancreas-Tx per mill. popula$on Sec$on for Transplant Surgery

7 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

8 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

9 Pancreas-Tx in Norway: HISTORY Era I: Era III: Era II: Era IV:

10 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

11 Pancreas-Tx in Norway: History ANTICOAGULATION Macrodex (Dextran) 500 ml Day Acetyl Salicylic Acid (ASA) from day Fragmin SPK ie un$l day ie un$l 6wks biopsy ASA from day 7

12 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$fungal prophylaxis and exocrine suppression Diflucan abandoned Sandosta$n abandoned Ulcus prophylaxis Somac 40 mg x 2 (first two weeks, then 40mg x1)

13 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 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 15 Hvorfor så streng seleksjon på donor og recipientsiden? Komplikasjoner/reoperasjoner Graftsurvival Pasientsurvival

16 UNordringer Short term: KIR. KOMPLIKASJONER Long term: REJEKSJONER

17 FUTURE STUDIES Ques$ons to be adressed Prospec$ve PTx study started in Oct 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?

18 Preliminary data ongoing PTx-study > N = 67 (per ): 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

19 Lindahl et al. Diabetologia 2013 Sec$on for Transplant Surgery

20 PTx in Norway: Results I (Lindahl et al. 2013) Sec$on for Transplant Surgery

21 PTx in Norway: Results II (Lindahl et al. 2013)

22 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 < < <0.001 Recipient gender Treatment LDK (n=171) SPK (n=222) DDK (n=237) Reference < Reference Time on dialysis Transplant era (n=304) (n=326) < < <0.001 Donor age <

23 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

24 Horneland et al., Am J Transpl, 2015

25 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 / Pancreas venous thrombosis rate - Graft loss due to v. thrombosis 9 (22,5%) 5 (12,5%) 2 (5%) 2 (5%) 0.048* Rejection rate; biopsy-verif. (# pts) - Total # of rejections treated 9 (22,5%) (25%) Pancreas Graft loss 8 (20%) 5 (12,5%) Kidney Graft loss (SPK) 1 (2,5%) 1 (3,3%) Patient death 1 (2,5%) 3 (7,5%) 0.615

26 Grax Survival Singel vs Kombinert PTX Sec$on for Transplant Surgery

27 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 ( ) ( ) HLA -A+B mismatches - DR mismatches 0.038* ( ) 0.76 ( ) ( ) - Patient death Recipient age 0.009* 1.21 ( ) 0.066* 1.24 ( ) Binary logistic Regression Dependent var.: Reoperation Per patient; (one or more reop.) Time on waiting list 0.008* 1.00 ( ) ( ) HLA -A+B mismatches - DR mismatches Independent variables w/ statistical significance at p < 0.15 included 0.038* p 0.33 ( ) 0.36 ( ) Univariate analysis Odds Ratio (95% CI) p 0.51 ( ) - Multivariate analysis Odds Ratio (95% CI) Recipient BMI 0.040* 1.17 ( ) 0.039* 1.30 ( ) Donor age: - Continous var. - <50 vs > 50 - <45 vs > 45 - <40 vs > * 0.035* 0.005* 0.042* 1.04 ( ) 3.41 ( ) 4.16 ( ) 2.61 ( ) 0.021* 1.08 ( )

28 The duodenoduodenostomy: Sten$ng the pancrea$c duct

29 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

30 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!