A Demetris

A Rao

Abu-Elmagd

C Janov

Casavilla

Fontes

Furukawa

G Mazariegos

Hosenpud

Howard

J Bueno

J Colangelo

J Reyes

J.J Fung

K.M Abu-Elmagd

Murase

Starzl

T.E Starzl

Tanabe

Todo

PubMed

Crossref

Evolution of clinical intestinal transplantation: improved outcome and cost effectiveness

Abu-Elmagd, K

Reyes, J

Fung, JJ

Mazariegos, G

Bueno, J

Janov, C

Colangelo, J

Rao, A

Demetris, A

Starzl, TE

Name not available

Abu-Elmagd, KM

D-Scholarship@Pitt

{ I , , ; i I I I !, . ---.-----------------------------2!iiiiiii ..(.:j- 07/ ELSEVIER Evolution of Clinical Intestinal Transplantation: Improved Outcome and Cost Effectiveness K.M. Abu-Elmagd, J. Reyes, J.J. Fung, G. Mazariegos, J. Bueno, C. Janov, J. Colangelo, A. Rao, A. Demetris, and T.E. Starzl I N PREVIOUS REPORTS we identified several risk factors that significantly affected patient and graft sur-vival.!.:! Of these. four were major Immunologic risk factors: the number of intestinal allograft rejections. high blood FK 506 levels. high dose steroid requirements. and the need for adjunct OKT3 therapy. The remaining significant risk fac-tors were the operative and cold ischemia times. number of previous abdominal surgeries. cytomegaloviral (CMV) and post-transplant Iymphoproliferative diseases. To decrease the immunosuppressive requirements and improve survival outcome. we declared a I year moratOrIum in 1994. pending the results of extensive clarifying investigations bv Murase et al in rats:1 When the p~og;am reopened. ~o major changes in management strategy were instituted. One was an attempt to avoid, when possible. the transplantation of organs from CMV-positive donors to C:'1V-negative recip-ients. The second change was to give perioperative adjunct donor bone marrow when this was available. in order to take advantage of the more tolerogenic profile of bone marrow cells compared to that of the IIltestinal passenger leukocytes:1- o Other adopted strategies were careful pa-tient selection. exclusion of the cnlon from the intestinal allograft. and monitoring of Epstein-Barr virus (EBV) infection by serial quantitative EBV polymerase chain reaction (peR) measurements. MATERIALS AND METHODS We report here our overall long-term results With 115 intestmal transplantation in 109 consecutive pallents that were transplanted over S years. Of these b4 ER9r~F were children and 45 (41 '.''') were adults. The causes of intestinal failure were short gut syndrome (SGS) in 119 Epl~FK dysmotility syndrome in II (10','",). intestinal neoplasm in 0 (0%). and enterocytc dvsfunction in 3 (3%). The leading causes of SGS were vascular occlUSion. Crohn's disease. and trauma in adults and volvulus, ga~troschisisK atresia and necrotizing enterocolitis in children. The intestlIlc was engrafted alone (n 43). or as part of a compOSite gratt (n = 72). before and after the moratorium. All of the is()lated intesllnal recipients were sutferin1! from frequent ccntralllIlc SCpSIS. vamshing central venous access. and reversihle tOlal parenteral nutrition (TPN) Induced hepatlc dvstunctlon. The d()n()rs .... ere all ABO identical and liLA histolI1cllmpatlhlc. The ivmphllcvtotoxic crossmatch was posltlve 1I1 14 paucrns. :"<,, attempts V'l're made to alter the graft Ivmpllllrc-ticular tissue with antllvmph()cvte preparations or other modalities. 0041 -1 345/99/$-see front matter PI! S0041-1345(98)0 1565-6 582 Of the last 55 recipients. 23 were infused with bone marrow. the distinction from the other 32 being the willingness of the donor family to permit the extra procurement procedure. The surgical techniques of the donor and recipient operation and details of bone marrow augmentation are fully described elsewhere.7- lO The management of the intestinal allograft recipients is fully described elsewhere. 11 The immunosuppressive therapy was based on FK 506 and prednisone. Cyclophosphamide was given to 23 patients after the moratorium at a dose of 2 to 3 mg/kgld for 4 weeks and then switched to mycophenolate mofetil (15 to 30 mgJkgJd) or azathioprine. In a few cases. azathioprine was given as a third drug from the outset. The level of mamtenance immuno-suppression was individualized and adjusted hased on the clinical course of each patient with the intentlon to reduce the drug dosage and levels whenever pOSSible. Episodes of rejection were treated with adjustments of FK 506 dose and/or supplemental prednisone. OKT3 was given only as a rescue therapy. Upward dose adjust-ments of mycophenolate mofetil. azathioprine. or steroids. were frequently needed to compensate for FK-506 dose reductions mandated hy FK 506-related adverse effects. Patient and graft survival curves were generated using the Kaplan-Meier method and group comparisons .... ere performed using the log-rank test. RESULTS Survival The overall cumulative patient survival is T2q at 1 year and -+~o/c at 5 years with a graft survival rate of M% and 40%. respectively. With a mean follow-up of ~KEF ::: 29 months (range. 1 to 94 months). 31 patients are alive with good nutrition heyond the third postoperative year and 18 are well he yond the 5-year mile stone. The survival benefits of intestinal transplantation has been hetter (P = .57) achieved among children compared to adults with the best outcome among patients he tween 2 and 17 years of age. in whom the 5-year cumulative survival rate was 68%. Al-though hoth the isolated intestinal and composite visceral grafts had similar (P = .72) survival rates. the cumulative risk of graft loss due to rejection was significantly (P = .045) higher among the isolated intestine. The Kaplan-Meier From the Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA. Address reprint requests to Dr Abu-Elmagd, University of Pittsburgh. Thomas E. Starzl Transplantation Institute, Falk CliniC. 4th Floor. 3601 Fifth Ave. Pittsburgh, PA 15213. © 1999 by ElseVier Science Inc. 655 Avenue of the Americas. New York. NY 10010 Transplantation Proceedings, 31. 582-584 (1999) EVOLUTION OF INTESTINAL TRANSPLANTATION Children 1.0.,..--------\ticro\illus (0=3) 0.8 : , -eo:! > .;: \.0 0.6 = Ir.i. -: , I ~ " Gastroschisis 10=161 , "EC (o=H) 1.0 0.8 583 Adults , = -,- 0.4 : , Crohn's (0=10) K~ 0.4 -eo:! Voh'ulus 10=18) :. I ........ Thrombosis (0=13) Q. : ___ !r,!l'!.ma (0=7) aysmolili~ (0=11) 0.2 Tumor (0=6) 0.0 -1-----,--------- 0.0 -I-----,----r----r----; o 2 .. 6802468 Time After Transplantation(years) graft survival curves stratified Jccording to the cause of intestinal failure are depicted in Figure I. The best survival rates have heen achieved among children with microvillus disease and gastroschisis and in adults with Crohn's disease and vascular thrombosis. Figure 2 ,hows the significant (P = .(4) improvement in intestinal allograft survival during the last four years (after the moratorium) with a cumulative rate of 65% at 4 years. Such an achie\ement reflects further refinement in operative techniques. immunomodulation. and postoperative management as descrihed above. Long-Term Rehabilitation Fifty-one (93%) of 55 current survivors are home. fully active. and completelv nIl TPN with full nutritional auton-omy. These individuals have reported improved quality of life measures in comparison to TPN dependency. Two (3.5 r r) of the remaining four recipients require home parenteral nutrition because of dmmic graft dysmotility. "i .. . s: ... = :rJ .::: ~ '-.. ~ 1.0 0.8 0 .• \ '\ 0.4 0.2 N=115 \ \ ... ... 1990-1993 (n=63) 199.$-1998 (n=52) ! p=O.04! .. 0.0+-----...,-----...,-----...-------, o Time After Transplantation (years) Fig 2. Graft survival before and after the 1994 moratorium. Fig 1. Graft survival according to the native intestinal disease. The other two (3.5%) patients are receiving partial intr,l-venous support while recovering from a recent episode of moderate to severe rejection. :--10 clinical or histopathologic evidences of disease recurrence has been documented during the 8 years of follow-up. To date. no attempts have been made to electively wean any of the intestinal recipi-ents. including the hone marrow augmented cases. off immunosuppression. Cost Analysis The avcrage cost of intestinal transplantation between 1990 and 1994 was 5203.111 for the isolated intestine. $252..+53 for the combined liver-intestine transplantation. and 5284.-152 for the multivisceral procedure. This has been significant Iv reduced during the last -I years to an average of 5132.285. S2l4.716. and S219.09K respectively. The use of intestinal transplant can he examined on a cost-effective-ness basis. due to the availahility of chronic TPN as an alternative therapy I'm patients with irreversible gut failure. Based on Medicare data. the average yearly cost of TPN in 1992 was more than 5150.000 per patient not including the cost of frequent hospitalization. medical equipment. and nursing care. 12 The total dollars spent on TPN are increas-ing every year hecause of the vearlv increase in TPN cost and the cumulative increas..: llf the home and hospital hound qm~ population. Based on these data. intestinal transplantation hecomes eost-ctfectivc bv the second year ;ltter transplantation. CONCLUSIONS I ntestinal transplantation has hecome a life-saving treat-ment for pall..:nts with Irreyersihk intestinal failure who canllot he maintained on TP:--I. and a cost-effective therapy for pallents who still have the optllln of TPN. The long-term rehahilitalloll with all threc kinds of intestinal transplant ~~ ~---~ -----------~---~ 584 procedures is similar to that achieved with lung transplan-tation l' (currently eligible for reimbursement by Medicare) and the other kinds of organ allografts. Therefore, it is justifiable, to consider intestinal transplantation as nonex-perimental procedure that is eligible for reimbursement under Medicare, Medicaid, and other third party payers in the United States, Based on the results of our most recent preclinical trials (unpublished data), further improvement in patient and graft survival is greatly anticipated with further immune modulation strategies (graft cytoreduction) that can be added to the bone marrow augmentation protocoL REFERENCES 1. Todo S, Reyes j, Furukawa H. et al: Ann Surg 3:270, 1995 2. Abu-Elmagd K Reyes 1. Todo S. ct al: J Am Coli Surg 186:512, 1998 3. MUTase N. Starn TE, Tanabe M. ct al: Transplantation 1>0: 158, 1995 ABU-ElMAGD, REYES, FUNG ET AL ~K Murase N. Oemetris AJ. Woo ], ct al: Transplant Proc 23:3246, 1991 5. Murase N, Oemetris AJ. Woo 1. et al: Transplantation 55:1. 1993 o. Tanabe M. Muasc N. Oemetris AJ . .;t al: Transplant Proc 26:4325, 1994 7. Starzl TE, Todo S. Tzakis A et al: Ann Surg 216:605, 1992 II. Casavilla A Selby R, Abu-Elmagd K et al: Ann Surg 216:605, 1992 9. Furukawa F, Abu-Elmagd K Reyes ], et al: Surgical Tech-nology International. Vol. 2. San Francisco: Universal Medical Press; 1994, pp 165-170 to. Fontes p, Rao A Oemetris AJ, ct al: Lancet 344:151, 1994 11. Abu-Elmagd K Fung 11, Reyes ], et al: Transplant Proc 24:1243, 1992 12. Howard L. Ament M, Fieming R, et al: Gastroenterology 109:355, 1995 13. Hosenpud 10. Novick R], Bennett LE. ct al: ] Heart Lung Transplantation 15:655, 1996 

Evolution of clinical intestinal transplantation: Improved outcome and cost effectiveness

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Evolution of clinical intestinal transplantation: Improved outcome and cost effectiveness

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