Canine Pancreas Allotransplantation with Enteric Drainage

Chi nese Med i cal Jour nal (Taipei) 2002;65:483-488 Orig i nal Canine Pancreas Allotransplantation with Enteric Drainage Yi-Ming Shyr 1 Cheng-Hsi Su 1 Anna Fen-Yau Li 2 Chew-Wun Wu 1 Wing-Yiu Lui 1 1 De part ment of Sur gery; 2 De part ment of Pa thol ogy, Tai pei Vet erans Gen eral Hos pi tal; and Na tional Yang-Ming Uni ver sity School of Med i cine, Tai pei, Tai wan, R.O.C. Key Words ca nine; en teric drain age; pan creas trans plan ta tion Background. Be fore em bark ing on a clin i cal hu man pan creas trans plan ta - tion pro gram we sought a ca nine an i mal model with en teric drain age to re - fine our tech ni cal skills, to eval u ate the sur gi cal risks and to study the re - jec tion pic tures un der mod ern tri ple immunosuppression ther apy. Methods. Twenty do nor-recipient pairs of un re lated mon grel dogs un der - went pancreaticoduodenal allotransplantation with en teric drainage. All dogs were immunosuppressed by triple therapy with prednisolone, cyclosporine (Neoral) and mycophenolate mofetil (MMF). Rejection grade and sur gi cal risk were eval u ated. Results. Group 1 in cluded 10 (50%) dogs surviving at least 14 days. In group 2 sur viv ing less than 14 days, the me dian sur vival was 5.5 days, rang ing from 1 day to 13 days. The most com mon com pli ca tions were du - odenal stump leak age and wound in fec tion. Duodenal stump leakage even tu ally led to mor tal ity in 3 dogs of group 2. Two (in group 2) of the 3 wound in fec tions be came too se vere to con trol and caused death. There were 2 dogs complicated with graft ne cro sis and 2 with graft vascular throm bo sis in di vid u ally, which all re sulted in death. Other fa tal com pli ca - tions in cluded 1 chyle leak age, 1 intraabdominal ab scess and 1 pneu mo nia in di vid u ally. Ninety per cent in each group de vel oped re jec tion. Se vere re - jec tion de vel oped in 5 (50%) dogs in group 2 (grade 4 and 5), p = 0.033, as compared with none in group 1. The rejection in most cases (90%) of group 1 was mild to mod er ate, with 4 grade 3, 3 grade 2 and 2 grade 1. Conclusions. Ca nine pan creas allotransplantation with en teric drain age is a fea si ble an i mal model to achieve sur vival lon ger than 14 days in 50% cases stud ied. Du o de nal stump leak age was the most com mon fa tal com - pli ca tion in this model. Se ver ity of re jec tion was closely as so ci ated with posttransplant fa tal com pli ca tions and played a cru cial role in de ter min ing the dog sur vival. [Chin Med J (Taipei) 2002;65:483-488] De spite the suc cess of ex og e nous in su lin ther apy, lots of long-term sequelae even tu ally de velop in pa tients with di a be tes, par tic u larly in su lin-dependent di a be tes mellitus (IDDM). The di a be tes-related com - pli ca tions may in clude nephropathy, neuropathy, retinopathy and microvascular dis or ders, which would po ten tially lead to ure mia, gas tric atonia, blind - ness, am pu ta tion, and pre ma ture death from myo car - dial in farc tion and cerebrovascular ac ci dents. The im - pe tus for pan creas trans plan ta tion is to pro duce a last - ing euglycemic state for en hance ment of qual ity of life, and to pre vent, ar rest or per haps re verse the in ex - o ra ble pro gres sion of the de struc tive ef fects of di a be - tes. 1 Re ceived: July 26, 2001. Ac cepted: June 26, 2002. Cor re spon dence to: Yi-Ming Shyr, MD, Di vi sion of Gen eral Sur gery, De part ment of Sur gery, Tai pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan. Fax: +886-2-2875-7537; E-mail: ymshyr@vghtpe.gov.tw

484 Yi-Ming Shyr, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 10 A ca nine model of pan creas allotransplantation with bladder drain age was well stud ied and es tab - lished. 2,3 Blad der drain age has been claimed to as so ci - ate with fewer im me di ate posttransplant com pli ca - tions than other meth ods, and clin i cally ap plied to IDDM pa tients for quite a long pe riod of time. 4,5 How - ever, with the rec og ni tion that long-term uri nary com - pli ca tions such as uri nary tract in fec tion, ure thral ste - no sis, ure thral dis rup tion, re flux pan cre ati tis and met - a bolic ac i do sis are fre quently as so ci ated with blad der drain age, the en thu si asm for this pro ce dure has di min - ished. 6 Con se quently, there is a trend to ward pri mary en teric drain age, a more phys i o logic ap proach. 6 How - ever, the ca nine model with en teric drain age was sel - dom men tioned and not well stud ied. 7 Be fore em bark ing on a clin i cal hu man pan creas trans plan ta tion pro gram we sought a ca nine an i mal model with en teric drain age to re fine our tech ni cal skills, to eval u ate the sur gi cal risks and to study the re - jec tion pic tures un der mod ern tri ple immunosuppression therapy. Methods Twenty mon grel dogs, weigh ing 15 to 24 kg, un - der went pan creas allotransplantation. Engraftment with a Car rel patch of aorta and cuff of por tal vein ne - ces si tated do nor sac ri fice af ter pro cure ment. All dogs were fasted for 12 hours. Pen i cil lin G, 1 mil lion U was ad min is tered intra mus cu larly at the time of op er a tion. An es the sia was in tra ve nously in duced with so dium pentobarbital (25 mg/kg) in do nor-recipient pairs on ad ja cent op er at ing ta bles. The dogs were intubated and main tained on a res pi ra tor. Procurement The ab do men of the do nor was en tered through a long midline in ci sion. Mo bi li za tion of the right pan cre - atic lobe was initiated by di vid ing the in fe rior pancreaticoduodenal ar tery which was from su pe rior mesenteric ar tery (SMA). The mesentery and small vessels along the me dial bor der of the right pan cre atic lobe were divided by cauterization. The su pe rior mesenteric vein (SMV) and su pe rior mesenteric ar tery (SMA) were dis sected out and freed from sur round ing tis sue. At ten tion was di rected to the left pan cre atic lobe. The splenic ar tery and vein were di vided. The mesentery and small ves sels along the up per and lower bor ders of the left pan cre atic lobe were di vided. The por tal vein was ex posed by di vid ing the com mon bile duct and mul ti ple proper hepatic ar ter ies. At this time, the gastroduodenal ar tery should be well pre served be - cause it was the main blood sup ply to the right pan cre - atic lobe and part of the left pan cre atic lobe. The prox i - mal du o de nal cuff was sta pled and transected with a GIA 50 Pre mium sta pling de vice (U.S. Sur gi cal Corp., Norwalk, CT, USA) just dis tal to the py lo rus. The ce - liac trunk and whole hepatic ar tery were freed out by di vid ing its sur round ing struc tures in clud ing the left gas tric ar tery and vein. The Car rel patch was pre pared by clear ing a length of aorta around the or i gin of the ce - liac trunk. Ad e quate ex po sure for aor tic clamp ing was gained by in cis ing di a phrag matic crura su pe ri orly. A seg ment of the infrarenal aorta was dis sected out and canulated. Then, the pan creas was perfused with 500 ml of cold UW (Uni ver sity of Wis con sin) so lu tion via infrarenal aorta af ter clamp ing the infradiaphragmatic aorta and SMA. The pancreaticoduodenal graft was re - moved by di vid ing the SMV be fore en ter ing the pan - creas, por tal vein near the bi fur ca tion, dis tal du o de nal cuff near the tail of the right pan cre atic lobe and aorta above and below the or i gin of the ce liac trunk. The graft was placed in iced sa line slush im me di ately and reperfused with ad di tional UW so lu tion un til the ve - nous ef flu ent was clear, usu ally 100-200 ml. The graft was im mersed in the cold UW so lu tion un til it was engrafted. Engraftment The re cip i ent was also en tered through a midline in ci sion. A seg ment of infrarenal aorta and in fe rior vena cava (IVC) was iso lated. Para-aortic lymphatics were me tic u lously li gated to avoid chylous ascites. An end-to-side por tal vein-to-ivc anas to mo sis was fash ioned with a run ning 6-O Prolene su ture. The ar - te rial anas to mo sis for the Car rel patch and aorta was fash ioned in a sim i lar man ner. To avoid graft hy per -

October 2002 Pan creas Allotransplantation 485 ten sion and min i mize sub se quent edema, the graft was reperfused by re leas ing the ve nous clamp prior to re stor ing ar te rial in flow. Exocrine se cre tions were drained into je ju num with ei ther side-to-side or end-to-side duodenojejunostomy (dis tal du o de nal cuff-to-upper je ju num). To avoid risks un re lated to pan creas trans plan ta tion such as du o de nal ischemia, du o de nal per fo ra tion and bile leak age, na tive to tal pancreatectomy was not per formed since the pur poses of this study were mainly to re fine our tech ni cal skills, to eval u ate the sur gi cal risks and to study the re jec tion pic tures. The ab dom i nal wall was closed in lay ers with run ning su tures. Postoperative care Dogs were kept on a warm ing blan ket over night. All dogs were fed ad li bi tum start ing from post op er a - tive day 1. If oral in take was in ad e quate, a 5% dex trose so lu tion was ad min is tered sub cu ta ne ously or in tra ve - nously. Pen i cil lin G, 1 mil lion U was administered intra mus cu larly twice a day af ter op er a tion. Each dog was immunosuppressed by tri ple ther apy con sist ing of (1) prednisolone (A-Methapred, Abbott Lab o ra tories, North Chi cago, IL, USA), 125 mg in tra ve nously dur - ing op er a tion and 0.4 mg/kg intra mus cu larly daily; (2) cyclosporine (Neoral) (Novartis Pharmaceutcals, Basel, Swit zer land), 10 mg/kg po dur ing op er a tion and daily; (3) Mycophenolate mofetil (MMF) (CellCept, Roche Phar ma ceu ti cals, Nutley, NJ, USA), 40 mg/kg orally dur ing op er a tion and daily. Se rum glu cose and am y lase were de ter mined on post op er a tive day 0, 1, 7 and 14. The study end-point was the post op er a tive day 14. Based on sur vival af ter trans plan ta tion, dogs were clas si fied into group 1 sur viv ing at least 14 days and group 2 sur viv ing less than 14 days. All the group 1 dogs were sac ri ficed over the post op er a tive day 14. Au topsy was per formed im me di ately af ter the days ex - pired to ex am ine the pan cre atic graft grossly and mi cro - scop i cally, to min i mize the post-mortem change, and also to as sess the cause of death in each group of dogs. Re jec tion grading Histologic grad ing for acute pan cre atic allograft re jec tion pro posed by Univeristy of Mary land Med i - cal Sys tems was ap plied: 8 Grade 0, nor mal: nor mal pan creas his tol ogy. Grade 1, bor der line: changes con sist ing of rare lymphocytic septal in fil trates while the acinar pa ren chyma is free of in flam ma tion. Grade 2, mild: mixed in flam ma tory septal in fil trates with fo cal in volve ment of acinar pa ren chyma (ductal in flam ma tion and/or venulitis are of - ten seen). Grade 3, mod er ate: septal in flam ma tion with multifocal in volve ment of acinar pa ren chyma as so ci ated with sin gle-cell in jury such as vac u ol iza tion, ne cro sis or apoptosis. Grade 4, mod er ate with vas cu lar in volve ment: mod er ate re jec tion with ar te rial endotheliitis or vasculitis. Grade 5, se vere: ex ten sive in flam ma tory in fil trates with con flu ent acinar ne cro sis. Sta tis ti cal anal y sis was car ried out by us ing the SPSS 8.0 soft ware pro gram (Sta tis tic Pack age for So - cial Sci ences, SPSS Inc. Chi cago, IL, USA). Data were pre sented as mean ± stan dard de vi a tion. Cat e - gor i cal vari ables were com pared by χ 2 test or Fisher s ex act test. Stu dent s t-test was used to com pare two means. Two way ANOVA (anal y sis of vari ance) was used to see the ef fects of two dif fer ent fac tors on the study groups, and Tukey test was used for mul ti ple com par i son if there was sig nif i cant dif fer ence. The P val ues less than 0.05 were con sid ered sta tis ti cally sig - nificant. Results Ten (50%) dogs as group 1 sur vived at least 14 days. In group 2 sur viv ing less than 14 days, the me - dian sur vival time was 5.5 days, rang ing from 1 day to 13 days. There were 7 male dogs in group1 and 9 in group 2, p = 0.264. As shown in Ta ble 1, it took 219 ± 25 min utes to pro cure and en graft the pancreaticoduodenal graft in group 1 and 227 ± 25 min utes in group 2, p = 0.484. There was also no sig - nif i cant dif fer ence in cold (20 ± 4 vs.18 ± 6 min utes, p = 0.390) and warm (39 ± 7 vs. 43 ± 10 min utes, p = 0.306) ischemic times be tween both groups. All of

486 Yi-Ming Shyr, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 10 pan creas grafts in both groups looked grossly vi a ble and had good blood per fu sion at the time of trans plan - ta tion. As shown in Ta ble 1, the pre op er a tive and post op er a tive blood sugar and am y lase lev els were not sig nif i cantly dif fer ent be tween both groups, but the am y lase lev els were sig nif i cantly higher on day 1 and day 14 than on day 0 (be fore op er a tion). As listed in Ta ble 2, com pli ca tion oc curred more in group 2 (4 in group 1 and 10 in group 2, p = 0.011). Most (80%) of the dogs in group 1 were sac ri ficed af - ter sur viv ing 14 days (Ta ble 3). The most com mon com pli ca tions were du o de nal stump leak age and wound in fec tion. Du o de nal stump leak age even tu ally led to se vere intraabdominal in fec tion re sult ing in mor tal ity in 3 dogs of group 2. Two (in group 2) of them had sep sis re sult ing in mor tal ity. Two dogs com - pli cated with graft ne cro sis and an other two with graft vas cu lar throm bo sis de vel oped intraabdominal in fec - tion and ex pired fi nally. One dog died of hypovolemic shock due to chyle leak age from the paraaortic re gion the day af ter trans plan ta tion. One dog in group 2 was com pli cated with intraabdominal ab scess re sult ing in death, but no ob vi ous ev i dence was found to be re - lated to the graft. Fa tal pneu mo nia de vel oped in 1 dog of group 1. Only 2 dogs were free of re jec tion, and 90% in each group were proved histologically to have re jec - tion (Ta ble 4). Five (50%) dogs (4 grade 4 and 1 grade 5) in group 2 de vel oped se vere re jec tion, p = 0.033, as com pared with no se vere re jec tion in group 1. Among Table 1. Blood sugar and amylase levels after canine pancreas allotransplantation with enteric drainage Group 1 Group 2 p value (between days) Blood sugar level 0.051 day 0 87 ± 12 99 ± 23 day 1 84 ± 12 81 ± 23 day 7 91 ± 14 109 day 14 97 ± 10 p value (between groups) 0.287 Blood amylase level < 0.001 a day 0 1230 ± 283 1231 ± 340 day 1 1846 ± 997 3476 ± 1487 day 7 2076 ± 1159 368 day 14 2748 ± 1281 p value (between groups) 0.077 Group1: surviving atleast 14days; group2: surviving less than 14days. a Tukey test for multiple comparison after two way ANOVA showed significant difference for blood amylase levels between day 0 and day 1, and between day 0 and day 17. Table 2. Complications after canine pancreas allotransplantation with enteric drainage Total Group 1 (survival 14 days) Group 2 (survival < 14 days) Number of the dog with complication a 14 4 10 Duodenal stump leakage 3 0 3 Wound infection 3 1 2 Graft vascular thrombosis 2 0 2 Graft necrosis 2 1 1 Chyle leakage 1 0 1 Intraabdominal abscess 1 0 1 Pneumonia 1 1 0 Intraabdominal bleeding 1 1 0 a p = 0.011 between group 1 and 2, by Fisher s exact test.

October 2002 Pan creas Allotransplantation 487 Table 3. Causes of death after canine pancreas allotransplantation with enteric drainage Total Group 1 (survival 14 days) Group 2 (survival < 14 days) Sacrificed 8 8 0 Intraabdominal infection 8 1 7 Sepsis 2 0 2 Hypovolemic shock 1 0 1 Pneumonia 1 1 0 Table 4. Rejection patterns after canine pancreas allotransplantation with enteric drainage Rejection grade Total Group 1 (survival 14 days) Group 2 (survival < 14 days) Grade 0 2 1 1 Grade 1 5 4 1 Grade 2 4 3 1 Grade 3 4 2 2 Grade 4 4 0 4 Grade 5 1 0 1 the group 2, 2 cases of the grade 4 re jec tion were as so - ci ated with vas cu lar throm bo sis, 1 grade 4 with du o - de nal stump leak age and 1 grade 4 with graft ne cro sis. The dog with grade 5 re jec tion had se vere wound in - fec tion. Re jec tion in most cases in group 1 (90%) was mild to mod er ate, 4 at grade 1, 3 at grade 2 and 2 at grade 3. Graft ne cro sis in group 1 was as so ci ated with grade 3 re jec tion. Discussion The re sump tion of nor mal glu cose ho meo sta sis through pan creas trans plan ta tion pro vides sev eral ben e fits. First, and per haps most im por tantly, qual ity of life is im proved. 9 Sec ond, as dem on strated by the Min ne sota group and oth ers, the re cur rence of di a - betic nephropathy is at ten u ated. 9,10,11 Third, di a betic retinopathy is re duced. 12 Fourth, the pro gres sion of di - a betic neu rop a thy may be halted and in some cases re - versed. 13,14 This in cludes im prove ments in au to nomic neu rop a thy, as well as en hance ments of both car diac re flex func tion and gas tric mo til ity. 14 Even di a betic vesicopathy has shown to im prove af ter pan creas transplantation. 15 Finally, di a betic car dio vas cu lar dis - ease is also at ten u ated af ter pan creas trans plan ta tion. 16 Now a days, pan creas transplant cen ters in the United States can usu ally achieve a suc cess rate over 80% in the 1-year allograft sur vival of hu man pan - creas trans plan ta tion ap proach ing that of kid ney transplantation. 6 These en cour ag ing out comes should prompt de vel op ment of new pan creas trans plan ta tion pro grams all over the world. As with any or gan trans - plan ta tion pro ce dure, tech ni cal ex per tise can be achieved and re fined only through ex pe ri ence, which can be gained with the aid of a good an i mal model sim u lat ing clin i cal con di tions. 2 Our ca nine pan creas allotransplantation with en teric drain age is a fea si ble an i mal model, in which 50% could sur vive at least 14 days un der mod ern tri ple immunosuppression ther - apy. This study pro vides a valu able an i mal model closely re sem bling the tech nique used in hu man pan - creas trans plan ta tion. 6 With the same sur gi cal tech nique and sim i lar sur - gi cal pa ram e ters in this ca nine model, our ex pe ri ence clearly in di cates that se ver ity of re jec tion was closely as so ci ated with posttransplant fa tal com pli - ca tions, par tic u larly vas cu lar throm bo sis and graft ne cro sis. Five (50%) dogs in group 2 de vel oped se - vere re jec tion (grade 4 and 5). In con trast, there was

488 Yi-Ming Shyr, et al. Chi nese Med i cal Jour nal (Taipei) Vol. 65 No. 10 no se vere re jec tion in group 1 (p = 0.033). There were 4 com pli ca tions in group 1 and 10 in group 2 (p = 0.011). All of the 10 com pli ca tions in group 2 and 2 of the 4 in group1 were fa tal. Among these fa tal com - pli ca tions, du o de nal stump leak age was the most com mon, fol lowed by graft vas cu lar throm bo sis and graft ne cro sis. These find ings were sim i lar to those in hu man pan creas trans plan ta tion. 6 There fore, graft re jec tion played a cru cial role in de ter min ing the dog sur vival. How ever, the key fac tor af fect ing graft re - jec tion re mained un de ter mined in this study. The prob lems might be in histocompatability be cause we used the un re lated do nor-recipient pairs of mon grel dogs and/or in ad e quate immunosuppression in which only prednisolone was given by more re li able in tra ve nous and in tra mus cu lar routes, while the other two immunosuppresssants, cyclosporine and mycophenolate mofetil, on day 1 and day 14 were given orally. In con clu sion, our ca nine pan creas allotransplantation with en teric drain age closely re sem bling the tech - nique used in hu man pan creas trans plan ta tion is a fea - si ble an i mal model, in which 50% could sur vive at least 14 days un der mod ern tri ple immunosuppression ther apy. Du o de nal stump leak age was the most com - mon fa tal com pli ca tion, fol lowed by graft vas cu lar throm bo sis and graft ne cro sis. Se ver ity of re jec tion was closely as so ci ated with posttransplant fa tal com - pli ca tions and played a cru cial role in de ter min ing the dog sur vival. Referrences 1. 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Ad van tage of blad der drain age in pan creas trans - plan ta tion: a per sonal view. Clin Tanspl 1990;4:32-6. 6. Sollinger HW, Odorico JS, Knechtle SJ, D alessandro AM, Kalayoglu M, Pirsch JD. Ex pe ri ence with 500 si mul ta neous pan creas-kidney trans plants. Ann Surg 1998;228:294-6. 7. Diliz-Perez HS, Hong HQ, de Santibanes E, Bedetti C, Iwatsuki S, Shaw BW, et al. To tal pancreaticoduodenal homo trans plan ta tions in dogs immunosuppressed with cyclosporine and ste roids. Am J Surg 1984;147:677-80. 8. Kou PC, John son LB, Schweitzer EJ, Klassen DK, Hoehn-Saric EW, Weir MR, et al. Sol i tary pan creas allo - grafts. The role of percutaneous bi opsy and stan dard ized histologic grad ing of re jec tion. Arch Surg 1997;132:52-7. 9. Adang EMM, Engel GL, van Hooff JP, Kootstra G. Com par i - son be fore and af ter trans plan ta tion of pan creas-kidney and pan creas-kidney with loss of pan creas. A pro spec tive con - trolled qual ity of life study. 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Laftavi MRA, Chapuis F, Rahbar M, Lefrancois N, Feitosa LC, Dubernard JM, Mar tin X. Di a betic polyneuropathy out - come af ter suc cess ful pan creas trans plan ta tion: 1- to 9-year fol low-up. Transpl Proc 1995;27:1406-9. 15. Mar tin X. Im prove ment of di a betic vesicopathy af ter pan cre - atic trans plan ta tion. Transpl Proc 1995;27:2441-3. 16. Cheung ATW, Perez RV, Basadonna GP, Cox KL, Bry WI. Microangiopathy re ver sal in suc cess ful si mul ta neous pan - creas-kidney trans plan ta tion. Transpl Proc 1994;26:493-5.