Intestinal transplantation, solitary (n = 3) or in combination with the liver (n = 7), was performed in 10 pediatric patients with intestinal failure. The liver was only replaced if there was liver failure and portal hypertension. Immunosuppression was based on FK 506. Two patients died, one of graft-versus-host disease and one of lymphoproliferative disease. One patient was still in the intensive care unit 1 month posttransplantation due to perioperative complications. The function of the intestinal grafts in the remaining patients is normal. All nutrition and medications including immunosuppression are being administered enterally. This series indicates that small bowel transplantation, alone or in combination with the liver, is feasible in pediatric patients. © 1993

Adrian Casavilla

Andreas G. Tzakis

Anthony J. Demetris

Bakr Nour

David H. Van Thiel

Eduardo Yunis

Goulet

Grant

Iwaki

Jorge Reyes

Kareem Abu-Elmagd

Murase

Rick Selby

Samuel Kocoshis

Satoru Todo

Schraut

Shaffer

Starzl

Thomas E. Starzl

Todo

Tzakis

Zhong

English

PubMed

Tzakis, AG

Todo, S

Reyes, J

Nour, B

Abu-Elmagd, K

Selby, R

Casavilla, A

Kocoshis, S

Demetris, AJ

Yunis, E

Van Thiel, DH

Starzl, TE

Name not available

Intestinal transplantation in children under FK506 immunosuppression

Crossref

Intestinal transplantation in children under FK 506 immunosuppression

D-Scholarship@Pitt

Intestinal Transplantation in Children Under FK 506 Immunosuppression By Andreas G. Tzakis, Satoru Todo, Jorge Reyes, Bakr Nour, Kareem Abu-Elmagd, Rick Selby, Adrian Casavilla, Samuel Kocoshis, Anthony J. Demetris, Eduardo Yunis, David H. Van Thiel, and Thomas E. Starzl Pittsburgh, Pennsylvania • Int.stinal tr.n.pl.ntation, solitary In = 3) or in combina-tion with the liv.r In = 1), w •• performed in 10 pediRrie patients with intesti .... failure. Th. liver w •• only rept.ced if th.re w •• liver f.ilur •• nd portal hypert.nsion. Immunosup-pression w •• b.sed on FK 501. Two patients died, on. of gr.ft-v.rsus-host di..... .nd on. of Iymphoprolif.retive di...... On. p.ti.nt wu .till in the int.nsive care unit 1 month po.ttr.n.plentetion due to perioperetiv. complica-tion •. The function of the intestinel grafts in the rem.ining p.tient. is norm.1. All nutrition and medicetion. including immuno.uppression .re being administered enterelly. Thi. serie. indicate. th.t .m.1I bow.1 transpl.ntation, .Ion. or in combination with the liver, is feasible in pediatric patients. Copyright c 1993 by W.B. SIIund.,. Compeny INDEX WORDS: Intestin.1 tr.n.plant.tion; liver tran.pl.nta-tion; FK S06 immunosuppression. CADAVERIC intestinal transplantation in combi-nation with the liverl•2 or alone3•4 is now practi-cal and reproducible4 and promises to revolutionize the treatment of intestinal failure as liver transplanta-tion did for liver failure more than 10 years ago. Optimism has been moderated mainly by the complex-ities of the procedure and its postoperative course. The first example of a functional human intestinal transplant was not achieved until 1987 in a child who underwent multivisceral transplantation under cyclo-sporine.5 When this and a second patient died of lymphoproliferative disease. a moratorium on intesti-nal transplantation was declared at the University of Pittsburgh until FK 506 immunosuppression became available. The pediatric and adult series were devel-oped contemporaneously. The longest surviving child, the recipient of a combined liver-intestinal graft 2 years ago,6 has enjoyed a norma11ife style for essen-tially all of her postoperative life. From the Depanment of SUIJf!'Y, Univusity Health Center of Pinsburgh, UnivtrlllV of Pittsburgh, and the Vett1YJIU Administration Medical Center. Pinsburgh, PA. Presented at the 39th AnnUilI IntemlJtionai Congress of the British AssociatIOn of Paediatric p~K Leeds, England.. July 15·18, 1992. Supported in parr bv research grantS {rom the Vett1YJIU Administra-tion and Project Granl No. DK 29961 from the NationalllUtiIutu of HeaWz. Bethescla. MD. Adiin!ss "pnnt "quests to Thomas E. Stani. MD, PhD. Depan-ment of Surgery, Uniw:niIy of Piltsbwgh, 3601 Fifth Ave, Pittsburgh, PA 15213. CowJ8ht c /993 by WB. S4IuuUn Company 0022-J.468193128OlJ..OO19S03.0010 1IMO We are presenting our whole experience with pediatric intestinal transplantation under FK 506 immunosuppression, with emphasis on the unex-pected ease with which isolated intestinal transplanta-tion has been accomplished. MATERIALS AND METHODS Selection of Recipients All recipients had intestinal insufficiency and were dependent on total parenteral nutnUon (TPN) for survival. ReCIpients of the combined graft had advanced TPN-induced liver dIsease and ponal hypenenslon. History of jaundice did not qualify the patients for liver grafting. Donors Donors were heart-beatlng cadavers of identical ABO blood group and similar size. HLA typtng was random. Proturement of the organs was pan of multiple organ harvesting. Preservation was with the University of Wisconsin solution. The small bowel from the ligament of Treitz to the ileocolic valve was used. No effort was made to ablate the donor's lymphatic tIssue. nor was any luminal flushing performed. Principles of Recipient Procedure All of the intraabdominal transplant procedures IOvolving more than one organ are variations of an experimental procedure called multivisceral transplantation.; Anerialization of the grafts was by anastomosis to the infrarenal aorta. The outflow of the solitary intestinal grafts was into the reCipient portal svstem. either by anastomosIS to the nallve supenor mesenteric vem or. in cases with previous abdommal operations, by placing the graft piggy back onto the extrahepatic ponal vein by means of end to side anastomosis.8 In combined liver-intestinal grafts the outflow was through the hepatic veins and into the inferior vena cava. The native ponal vein was drained into the donor ponal vein except patient 1. in whom it was drained into the inferior vena cava. Intestinal continuity was established (except in patient 4. who had an atretic rectum) by anastomosing the proxunal end of the donor gut to the recipient's upper gastrointestinal tract. The distal end of the donor gut was brought out on the abdominal wall as an ileostomy. The proximal end of the recipient'S colon was anasto-mosed end to side to the donor distal ileum. A feeding jejunostomy was performed in the last 3 cases. If a gastrosotmy preexisted. it was left intact (n = 2). Monitoring of Rejection Monitoring of rejection for the liver was as in liver transplanta-tion. For the intestine. mucosal biopsies were performed with a cup forceps near tbe stoma or with endoscopy. Multiple samples were obtained twice per week for a month. then at decreasing frequency aDd wben c:1iDic:alIy iDdicated. • f INTESTINAL TRANSPlANTAl10N USING FK 5011 Prevention of Rejection Prevention of relection was based on FK 506 and steroids. All patients were stan~d on the same dose of FK 506 (0.15 mg/kg/d) intravenously at the time of transplantation as a continuous infusion. When enteral feedings were tolerated FK 506 was given enterally at 0.3 mgl kgld in 2 divided doses. The dose of FK 506 was reduced in the face of deteriorating renal function and was mcreased in the facc of rejection. Blood levels were obtained daily at first. then at decreasing frequency. The desirable blood level was thought to be 1 to 3 ng/mL The steroid dose was different in the two groups. A bolus of hydroconlsone (1,000 mg) was given intraoperatively in the cases of solitary intestinal transplantation. followed by methylpredniso-lone (100 mgld) tapered to baseline within 5 days. The recipients of combined grafts received only the baseline dose which was common to the 2 groups: 20 mgld for patients over 10 kg of body weight and to mg/d for patients less than 10 kg. Steroids were iunher decreased or stopped if there was no rejection. Prostaglandm El (Prostin VR: Upjohn. Kalamazoo. MI; 0.6 to 0.8 ng/kg/h) was given intravenously for at leastS days. Treatment of Rejection Augmentation ot the baseline immunosuppression was consid-ered first including the addition of Azathiopnne if thought to be necessary. The mam mdication for this was FK 506 nephrotoXIcity. Dependmg on the seventy of the reJection. a bolus at sterOids or a steroid taper were also gIven. OKT3 was not used in any of these cases. Graft-versus-host disease (GVHO) was diagnosed once (case 4) and treatment was unsuccessfully attempted wilh intravenous FK 506 and Steroids. Prevention of Infection All donors received polymyxin. tobramycin. and amphotericin via the nasogastric tube. The recipients received the same regimen postoperative Iv unless there was bactenal growth on stool cultures greater than 10' insensitive to these antibiotics. In these cases the appropriate anubiotlcs were given. Broad-spectrum Intravenous antibiotics (Ampicillin and Cefo-taXJme, were given to both donor and recipient. the latter for 5 days. Nutrition Intravenous nutrilton was used liberally when enteral nutrition was not sufficient to cover the requlTements of the child. 100t1 Enteral nutrition was started as soon as there was evidencc of intestinal function. The solution used was full strength peptamen. (Qinitec) gradually increased in volume to cover the nutntional requirements. The volume. pH, and glucose content of the ileal output were monitored. If there was no rejection or bacterial overgrowth evident. rapid transit was treated with pharmaoologic agents. If mere solidification of the stool was needed pectin was added to the peptamen. Absorption Studies The O-xylose absorption test was performed at least monthly. FK 506 blood levels were also used as an tndicator of the absorptive ability of the intesttnal graft. RESULTS Ten children received intestinal transplants: seven in combination with liver and three solitary. All patients who received a liver graft had advanced cholestatic disease and all had varying degrees of portal hypertension. All patients had been dependent on TPN since birth. There were 6 female and 4 male patients. Their ages ranged between 6 months and 10 years. Intesti-nal failure had been caused by necrotizing enterocoli-tis in 3 patients, midgut volvulus in 3, and gastroschi-sis, intestinal atresia, microvillus inclusions disease. and intestinal pseudoobstruction (1 case of each). All had had extensive previous abdominal surgery (ex-cept patient 7) (Table 1). Patients who underwent the combined transplant required a longer stay in the intensive care unit and developed more episodes of rejection and infections than the solitary intestinal recipients. They also required a longer time before they could be indepen-dent of intravenous feeding (Table 2). Current immunosuppressive doses are similar in the two groups. Except for the patient in the intensive care unit (patient 10), all other patients have normal D-xylose absorption studies (Table 3). Tabla 1. Cllnlc8l Chllracuristla and Type of Tr8",,",," Patient No. III IV V VI VII VIII IX X Age at TX (mol 38 52 33 6 13 19 31 14 123 18 Primary NEe Galtro- NEe sa and Midgut Midgut Micro· Midgut Intestinal NEC disease schisis colon volvulus VOlvulus villous volvulus pseudo-atresia inclusions obstruction PreviOUS sa resec-' 58 resec- 58 resec· Total 58 + right 58 rasec· none 58 rasec· Gastrectomy, 58 rasec-surgery tlon, tion tion entero· colectomy. tion tion colectomy tion jejunos· colectomy duodenos-tamv tomy TypeofTX LSBT LSBT LS8T LSBT LS8T LS8T S8T S8T SBT LSBT Date 7190 11/90 3191 8/91 8/91 8/91 11/91 12/91 3192 5/92 (monthlyearl ~lions: TX, transplanWion; NEC. necrotiZing enteroGOlitis; SB.small bowel; LSST. combined liver-intastinal tranaplant.l1ion; SBT.IOliUlry small bowel transplantation_ 1042 TZAKIS ET AL rable 2. Postopentive CoUrM PatIent No. ICU stay Id) HOSPital stay (mo) Rejection Ino. of episodes I Infections Complete enteral feeding (days posttransplanll 4 3 7 60 4 3 4 'I 210 III IV 3.45 23 I 1.5 7 19 200 • Patient receiving a course of IV hyperallmentation supplement. tTPN currently slowly tapered. Two patients died. both recipients of the combined graft. Patient 3 had a complicated postoperative course. initially due to right phrenic nerve injury and paralysis of the right hemidiaphragm. Treatment required a tracheostomy and prolonged care in respi-ratory unit. He subsequently developed multiple episodes of rejection. treated with augmentation of the baseline immunosuppression and high-dose ste-roids. He later developed pleomorphic lymphoprolif-erative disease confirmed by allograft intestinal bi-opsy and died of liver failure 13 months after transplantation. Patient 4 had IgG deficiency at the time of trans-plantation and was found to have Pneumocvstis carinii pneumonitis on the second posttransplantation day. The course was further complicated by a leak from the gastro (recipient )-jejunal (donor) anastomosis. The leak was repaired and the immunosuppression reduced. Erythema of the abdominal wall developed in the absence of further anastomotic leak. Multiple skin biopsies failed to demonstrate GVHD except on posttransplant day 21 when apoptosis was noted. Treatment was ineffective and the patient died of multiorgan failure. Other complications included a pleomorphic lym-phoma (patient 6) 9 months after transplantation and Epstein-Barr virus meningitis (patient 2) complicated V 3 6 4 3 60 VI VII 130 7 4.3 2 2 2 8 7 45 49' VIII 5 2 o 14 IX 11 Still in hospital 3 o t X Still inlCU Still in ICU by a spinal hematoma (which resulted in paraplegia) after a spinal tap. Patient 7 developed jaundice 4 months after soli-tary intestinal transplantation. Cholangiography. liver. skin. rectal. and gastric biopsies have so far failed to show its cause. All except patient 8 demonstrated a recalcitrant refusal to eat. which persisted for several months after transplantation. Patient 8 alone among the receipients was eating voraciously before transplanta-tion. DISCUSSION Increasing experience with intestinal transplanta-tion indicates that it is feasible in children. alone or in combination with the liver. It is indicated when enteral nutrition is not possible. Adequate mapping of the pathology is important in order to ensure that the remaining viscera will per-form adequately. In the present patients this was particularly true in the cases of atresia. microvillus inclusion disease. and intestinal pseudoobstruction. To avoid the metabolic effects of the Eck fistula. a recognized complication of systemic portal drainage. hepatopetal portal venous drainage was chosen in all cases (except the native portal drainage in patient 1). Immunological advantage for this type of venous rable 3. Current Condition Patient No. III IV V VI VII VIII IX X FK 506 level 1.1 0.4 Dead Dead 1.4 0.1 2.3 0.6 1.0 Information not available Prednisone dose 0 0 0 0 5 0 5 Img/d) D·xv1ose Normal Normal Normal Normal Normal Normal Normal absorption FK 506 dose 0.1 O. I 0.3 0.1 0.6 0.12 0.2 (mg/kg/BID) ---_._. ----_._----INTESTINAL TRANSPlANTATION USING FK 506 drainage. at least as it pertains to intestinal transplan-tation. has nor been shown.9-12 The liver was replaced only when there was end-stage liver disease. It was thought that the relative simplicity and safery of solitary intestinal transplanta-tion outweighed the potential immunologic advan-tage provided by contemporaneous liver transplanta-tion. Ablation of the donor lymphatic tissue was not attempted. It is now clear. particularly from data accumulated after intestinal transplantation, that a two-way traffic of dendritic cells and lymphocytes starts immediately after grafting. J3· I4 The result is replacement of donor lymphocytes by those of the recipient and spread of donor cell colonies in the recipient's tissues. IS The induction of this mixed chimerism is only possible 1043 under powerful immunosuppression. Manipulation of lymphocytes of either the donor or recipient could alter the balance. The sole case of GVHD seen was probably due to inadequate immunosuppression compounded by the recipient's immune deficiency. The results of this study imply that solitary intesti-nal transplantation may be equally or more effica-cious than combined liver-intestinal transplantation. This experience is also supported by the results in the adult population. If confirmed it would suggest that transplantation should be performed before liver damage occurs. It is not known if and to what extent TPN-induced liver disease is reversible after success-ful intestinal transplantation.J REFERENCES 1. Grant D. Wall W. Mimeault R. et al: Successful small·bowell :,ver transplantation. Lancet 335:181·184.1990 2. Todo S. Tzakls AG. Abu-Elmagd K. et al: Cadavenc small howe I and small bowel-liver transplantation m humans. Transplan-tation 53:369-376. 1992 :'-. Todo S. Tzakls AG. Abu-Elmagd K. et al: Intestinal transplan-tation in composite visceral grafts or alone. Ann Surg 216:223-234. 1992 - -.;. Goulet O. Revilion Y. Brousse N. et al: Successful small bowel transplantatIon 10 an infant. Transplantation 53:940-943. 1992 5. Starzl TE. Rowe M. Todo S. et al: Transplantation of multiple abdomlDal viscera. JAMA 261:1449-1457.1989 6. Tzakis AG. Todo S. Reyes J. et al: Liver and small bowel transplantation for short gut syndrome m a child. Transplant Sci 1:27-33. 1991 7 Starzl TE. Todo S. Tzakis A. et al: The many faces of muillvisceral transplantation. Surg Gynecol Obstet 172:335-344. 1991 ~K Tzakls AG. Todo S. Reves J. et al: Piggyback orthotopic IOtestlnal transplantallon. Surg Gynecol Obstet 176:296-298. 1993 q Murase N. Demetns AJ. Furuya T. et a1: Comparison of the small intestine after multivisceral transplantation and the small ,ntestme transplanted with penal versus caval dramage. Trans-plant Proc 24:1143-1144. 1992 -10. Zhong R. He G. Sakai Y. et al: Combined small bowel and liver transplantation in the rat: Possible role of the liver in preventing IDtestmal allograft rejection. Transplantation 52:550-576.1991 11. Shaffer D. Diflo T. Love W. et al: Immunologic and metabolic effects of caval versus penal venous dramage in small-bowel transplantation. Surgery 104:518-524.1988 12. Schraut WHo Araham VS. Lee KK: Ponal versus caval venous drainage of small bowel allografts: Technical and metabolic consequences. Surgery 99:193-198. 1986 13. Murase N. Demetris AJ. Matsuzaki T. et al: Long survival in rats after multivisceral versus isolated small bowel allotransplanta-tion under FK 506. Surgery 110:87-98. 1991 1';. lwaki Y. Starzl TE. Yagihashi A. et al: Replacement of donor lymphoid tissue in human small bowel transplants under FK 506 immunosuppression. Lancet 337:818-819.1991 15. Stanl TE. Demetns AJ. Murase N. el al: Cell migranon. chimerism. and graft acceptance. Lancet 339: 1579-1582. 1992 " tt i I 

http://d-scholarship.pitt.edu/4827/1/31735062112309.pdf

Intestinal transplantation in children under FK 506 immunosuppression

Abstract

Similar works

Full text

Available Versions

Name not available

Crossref

D-Scholarship@Pitt

Name not available