REVIEW

Small bowel transplantation: Current clinical status

DAVID SIGALET, MD, PIIO, FRCSC

D SJGALET. Small bowel transplantation: Current clinical status. Can J Gastroenterol 1991;5(4):154-160. W ith recent refinements in immunosup­pression techniques, the first successful reports of small bowel transplantation in humans have now heen ma<le, increasing interest in bowel t ransplantation among clinicians and patient:i alike. This article reviews recent J evelopments in umlerstan<ling of the functional capabilities an<l requirements for effective im­mune suppression in bowel transplantation. Both experimental an<l cl inical experience with transplantation are <liscusse<l, as are the areas which appear to

offer the most promise for future developments. Finally gui<lelines for consi<lera­tion of patient selection for this procedure are reviewed.

Key Words: Cyclosporine, Immune sup/Jression, Nutrient u/nake

Transplantation de l'intestin grele: Etat clinique present

RESUME: Grace aux tout <lerniers progres des rraitements immunosuppresseurs, on rapporte les premieres transplantations reussies du grele chez l'homme, et l' interer susc ite par cette intervention augmence tam chez les clin iciens que chcz les patients. Le present art icle passe en revue !'evolution recente Jes connaissan­ces portant sur les capacitcs fonctionnelles ainsi que les modal ires <l 'une suppres­sion immunitaire efficace clans la transplantation <le l' intestin. L'autcur cvoque !'experience clinique et experimentale a la fo is, et presente les domaines qui sembleraient les plus prometteurs. Finalement, ccnains critcres de selection Je& receveurs sont examines.

De/>anmem of Surgery, Univenity of Alberta, Edmonton, Alberra Correspondence and re/>Tinl.5 : Dr U Sigalet, Depcmmem of Surgery. Montreal Children\

Hospital , 2300 Tupper, Montreal, Quebec HJH I P3 . Telephone (514) 934-4400, Fax (5 14) 934-434 1

Received for />t1hl1cat1cm March 28, 1991 . Acce/ned)uly 17, /991

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T l IE SI !ORT BOWEL SYNDRl)MI

that re~ulcs from massive losses of smal l howel continues to he a difficult problem despite the c,)mnHm use of long term total parenteral nutrition (TPN). TPN is expensive (1 ), limit, the li festyle of the patient anJ the pacienc's fami ly (2), and requires con­tinued long term venous access. Lung term TPN in children 1s even mmc prohlcmatic, with increased nutrient requirements, difficulty with patient compliance, and the risk of as.,oc.. iatcd li ver damage, espec ially in the very young infant (3 ). Because of these fac­tors, the lifelong mortali ty from direct complicatiuns nf long term TPN in the pediatric age group exceeds 15% (4). ln rhe neonate, mass ive resection of the smnl I howcl most commonly results from such condirnms as nccrmizing entcrocolitis, malmtauon with vol­vulus, anJ strangulated abdominal wall defects (4). ln the adul t population, mas~ive howcl resection most com­monly resuh s from mesenteric vascular accidents, inflammatory bowel dise,N: and trauma (5,6). These condit i,1n,

result in a stable incidence of new patients who require long term nutri ­tional support.

Small bowel Lransplantation as a treatment for shorr bowel syndrome has been considered for many years, but only in the past year have successful attempts at bowel transplantation been reported (7,8). Inevitably, such resu lts provoke inquiry from patients and fam ilies about the applicability of ~uch new therapies to their own situation. Since the last major reviews of small bowel transplantation were pub I isheJ, much new information has been presented (9,10). This article will sum­marize the research which has led to

the success of the cases reported, the current Status of bowel transplantation for treatment of short bowel syndrome, and possible d irections that future developments may take.

EXPERIMENTAL TECHNIQUES AND MODELS

Transplantation of vascularized or­gans, including the bowel, was fi rst ar­tempted by the French surgeon Alexis Carrel ( 11). The problem of rejection was soon recognized, anJ interest lan­guished until the late 1950s, when Lillehei's grnup ( 12) in Minnesota in­vestigateJ the effects of ischemia on gut organs. They found that cooling and perfusion with heparinized saline would allow reliable preservation of the small bowel for 4 h; this preserved bowel coulJ be re-implanted and would function indefinitely as an autografL (12). Their model consisted of a one stage operation; the superior mes­enteric vesse ls were isolated, clamped and divided, and the bowel was flushed and then revascularizeJ using the mesenteric vessels of a s imilarly prepared recipient, re-establishing bowel continuity using end-co-end anastomosis of the native duodenum and ileum Lo the graft. They a lso used isolated loops of bowel placed in the neck, permitting the study of im­munosuppressive agents and graft func­tion in a controlled fashion such that rejection of the graft would nor lead to the death of the animal (13 ). They had no success with a llografts, and with others found minimal survival aJ-

Bowel transplantation

TABLE 1 Experimental models of intestinal transplantation

lmmuno-Model ~ression Outcome (reference) Rat: Syngeneic Nil Indefinite survival (22) Rat: Fully allogeneic Nil Rejection, death at day 14 (22) Rot: GVHD only possible Nil GVHD, death at day 14 (40) Rat: Fully allogeneic CsA 15 mg/kg/day Indefinite survival (22) Dogs: Fully ollogeneic Nil Rejection. death at day 12 ( 17) Dogs: Fully ollogeneic CsA 25 mg/kg/day 91 days average survival (only

three of 11 survived longer than 60 days) ( 17)

Pig: Fully ollogeneic CsA 15 mg/kg/day 12 l days overage survival

CsA Cyclosporine, GVHD Groff-versus~host disease

vantage using the immunosuppressants available at chat time - azathinprine and steroids (14-16).

The dog model was used to evaluate th e rejection process in detail, and after the introduction of cyclosporine in rhe 1970s, the orthotopic model of bowel transplantation in the Jog was the first used to assess the effects of cydosporine on small bowel transplantation ( 17, 18). The significant prolongation of graft survival demonstrated by Reznick er al (17,18) frnm ToronLo in a land­mark study wa~ encouraging, hut the overnll succe~s raLe wa~ low (further details are discussed in the secLion on immunosuppression).

The description of hetermopic bowel tramplantaLion in rhe rat by Monchik and Russell in 1971 ( 19) greatly facilitated study in this field. The rat model has since served as the standarJ for init ial inveHigation~ of im­munosuppression, function and tech­niques. T echnically, the procedure is similar to that descr ibed for larger animals, the main problem being the small size of the vessels. The aorta is used as the conduit for the superior mesenteric artery, and the grafr is reva~­cularized using rhe recipient's inferior vena cava and aorta. The bowel is left as a Thiry-Vi lla fistula with proximal and distal stomas (hereroropic graft). Initial attempts to re-establish gastro­intestinal continuity immetliately using the graft were plagued with a high failure rate (20); however, with ex­perience th is improved (21,22). This mndel then became the standard for

(indefinite survival In seven of 16) (39)

investigation of small bowel transplan­tation in rats. Within the rat model the availahility of genetically defined strains of animals has greatly faci li tated investigaLion of the immunological consequences of small bowel transplan­tation ( 18,23 ). The current availahil ity of monoclonal antibodies to various cell populations in the raL should pro­vide further valuable information.

The pig is an excellent model of h uman bowel physiology, with a more defined genetic lineage than the dog (24). Although earlier attempts had hecn made ( 2 5), Ricour and colleagues (26) were the first tn perform successful small howel transplantation in the pig and achieve :illogrnft ~urvival. The 1cchniques used paralleled those used in Lhe dog.

In reviewing reports of experimental models of small bowel transplantation, tine must remember that rejection responses and function vary consider­ably depending on the model. Inbred strains of rats have varying rejection responses, while outhrcd larger animals generally undergo a more vigorous reaction ( 13, 19,25). Simi larly, dif­ferent models within the same species may exhibit different rejection respon­ses: grafts drained via the portal circula­tion of the recipient may have a survival advantage, while caval drainage permits more vigorous rejec­Lion (27,28). This may be due to an effect of the liver on soluble antigen processing: liver transplantation has long heen known to permit the survival of subsequent grafts from the same

CAN] GA::-TROENTEROL VOL 5 NO 4 JULY/AUGUST 1991 155

SIG A LET

donor, with normal reJection of 'thi rd parry' grafts (29,30). Finally, graft sur­vival in heteroLOpic models does nor imply that the graft is necessarily capable t)f supporting Lhe animal nutri­tionally.

REJECTION AND GRAFT­VERSUS-HOST DISEASE

The histology of small bowel allo­graft rejection has been well described, and can be divided into three phases ( 19,3 1 ). In the rat at day 3, there is no change detectable with routine light microsct)py, but at days 6 and 7, lym­phocytes and plasma cells begin to in­fil trate the lamina propria. In phast· 11, over days 8 and 9, the mfiltrare inten­sifies and extends to the muscularis propria. There is associated shortening and blunting of the villi and scattered epithelial sloughing. In phase Ill, which occurs after the 10th Jay, there is complete mucosa! destruction and transmural infiltration with lympho­cytes and polymorphonuclear leuko­cytes. Rejection is similar in J ogs and pigs, but has an accelerated time course; rejection is complete by days 7 to9(l 2- H,26).

The small bowel is unique among transplanted vasculnrizeJ organs be­cause of the large population of im­munocomperent cells which can become activated following transplan­tation into a non-major hisrocom­patibility complex (MHC) identical recipient. This leads to a phenomenon known as 'graft-versus-host disease', in­itially described following bone marrow transplantation. This problem was recognized by the early investigators of small bowel transpl:rnrntitm ( 12), and examined in derail using inbred strains of rats (1 9). When both rejection and graft-versus-host disease me possible, rejection is the dominant resptinse; however, when animals are treated with potent immunosuppressants such as cyclospor'lne, graft-versus-host dis­ease becomes important. This results in an activation of graft-derived T cells directed against cell surface antigens of host epidermal cells (possibly primitive seem cell markers (32)). The disease complex seen after small bowel trans­plantation is a phase of poor appetite,

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red ears and snout, diarrhea, weight loss and hunched poswre, from which most animals recover spontaneously (31 ). There may be differences in the intes­tinal manifestations of the graft-versus­host disease seen after small bowel versus bone marrow transplantation (34 ); this possibility requires further in­vestig:ition.

REJECTION MONITORING In the clinical sening it is important

to monitor for rejection. The non­specific nature of the early stages of acute rejection noted above were found to limit the usefulness of suct ion biopsy in monitoring for rejection in the one clinical case that has been well docu­mented (35,36). This problem, coupled with the difficulty and possible hazards of obtaining biopsy material, have prompted invest igarors to search for al­ternate methods of monitt)ring for rejection. The functional capacity of the bowel has been exploited; the best characterized of these markers is the maltose absorption rest (37). This test measures the ability of the bowel mucosa co split maltose into glucose and then transport it across the enterocyte into the circulation, where it is detected hy monitoring of serum glucose levels. The resulting rise is diminished when rejection is in the in­itial stages.

A simpler methtx.l monitors changes in the permeability of the howcl wall by measuring the urinary excretion nf chromium-5 l EDT A instilled in the lumen of the graft. The bowel is nor­mally impervious to this compound; an increase in absorption occurs with early graft rejection (38). This test has been used clinically and has been found to correlate well with biopsy evidence tif rejection (7).

METHODS OF IMMUNOSUPPRESSION

At present, the factor which I imits the use of small bowel transplantation clinically is the lack of a reliable protocol for immunosuppression. After the description of the surgical techni­ques required for successful small bowel transplantation in dogs, a number of different immunosuppressants were

used, with limited success. These in­cluded steroids, azathinprme, anlt lym­phocyte globulin and graft irradiation (14-16,39). It was not until the intro· duct ion of cyclosporine in the late 1970s that a significant prolongation ti small bowel allograft survival was achieved ( l 7). The average survival in I J dogs treated with cyclosporine (25 mg/kg/day, tntramuscular injection for the first 28 days, then oral administra­tion) was 91 d,1ys, while umreated con­trols survived an average of 12. 5 Jays. However, it is important to note that only three dogs survived more than 60 days, and two of these succumbed to rejection at 210 days. The importance of using parenteral cyckisponne wa~ demonstrated in a fol ltlw-up study from the same group, in which a third set of animals was given oral cyclosporinc: seven of JO died of acute rejecllon an average of 30 days post transplant (18).

Once it had been shown that cyclospnrine prolonged the survival of intestinal allogrnfb in dogs, a serie~ of studies in the more controlled rat

model appeared. A dosage nf cyclo­~porinc of 15 mg/kg/day allowed indefi­nite survival of grafts in unidirectional and two-way rejection and grafL-versus· host dbca:,e models (22 ). A similar dosage of cyclosporine was ab() shown lO control grnfr,versus,host disease (40).

The model of bowel tramplantation available which most closely resembll's Lhc situmion in humans 1s the pig. Mnnotherary with high dosage intrn· vern)uscyclosporine ( 15 mg/kg/day) for LO days post transplant, followed by continued high dosage oral therapy (30 mg/kg/day) , has allowed successful trnnsplanrntion in chis model ( 41 ). These high dosages seem necessary: protocob ustng lower doses have an in­creased rmc nf ,mimal death, ;i i though this hns nnt been shown to he due to rejection (42). In the pig, combined stemid and cyclosporine use increased the rnte of infectious complications anJ did nor reduce the rat e of rejectton (4l) , while graft irradiation was nnc useful ( 43 ). It is interesting to note that stopp111g cyclosponne after two to three months of cominuous therapy did not lead to a llngrafr reject itln ( 41 ) . The

CAN J UASTROENTl:ROI \/l)I 5 Nt) 4 J UI Y/AlJ(,UST 1991

recipient may develop tolerance to the bowel a llografr in a fashion similar Ln

that described for liver transplams (29).

A tremendous effort ts underway to

improve methuJs of immunosuppre~­sion (44). These methods have in large part focused on pharmacological con­trol of rejection post transplantation. The new drugs FK506, rapamycin and 15-deoxyspergualin have already been shown to allow successful small hnwcl transplantation in rat models, and arc currently being reviewed in large an imal and human studies (45-47). Al­ternative strategics, such as pretreat­menl of grafr with monoclonal antibod ies ( 48) or o( host with donor­specific transfusion, arc also useful ex­perimentally ( 49). The challenge m present will be tn develop effective combined strategics which optimize both pretreatment of donor and recipient, and post transplamation im­munosuppression.

FUNCTION OF TRANSPLAN TED BOWEL

In the nrst studies of small howel tran plantation Li llehci and co­workers ( 12) showed t hat animals could survive indefinitely fo llowing autot ransplantation. No specific study of nutr ient absorption was performed, but gross malahsorption of fat wa~ evi­dent for two tu three weeks, and then suhsided. They were also able to demonstrate regeneration of severed lymphatics after three weeb (50). Ml>re detai led studies demonstrated that, fo llowing transplamation of the smal I bowel, dogs had a period of two to

three weeks of d iarrhea, weight loss and abnormal motility with steatorrhea. These changes reversed over the ensu­ing months; hy six momhs fu nction had normalized (51 ). An identical pmrern of changes cou ld he produced hy dener­vat ing the bowel and dividing the lym­phatics; it was concluded that the funct ion al alterariom of t rnnsplanin ­tion observed were due to denervation aml lymphatic disruption, and were re ­versihlc.

Several invest igawrs have ,hmvn that the t ransplanted bowel hccllmes electrically a utonomous, and that thb

may result in a reduction in glucose, glycine, water and sodium absorption (52,53). Chloride b most significmtly affected, with a net secretion in some instances, possibly due t1i a lo:;s of the nurmal inhibition of crypt chloride secretion by rhe autonllm1c nervous system following small howel trans­plantation. Limited studies ol bowel function al the cnterocyte level hnve been puhl ishcd: the dcctrophysio­logical parameters of the bowel seem norm.ii at nine days post transplam hut deteriorate rapidly if reJecnon 1lccurs (21).

In animab that arc nutritiunally dc­pcndem on a small howel transphmt, long term reductions in fat, protein and carbohydrate absorption have hcen demonstrated ( 54-56). Cyclosporine it­self may also affect nutrient absorption. Preliminary evidence wggcsts that cyclosporinc reduces glucose, alanine and fatty acid uptake in normal rnb,

and in autogrnfteJ bowel in dogs (56,57). Overall, these findings suggest that both the transplantation proce,, itself and rejection (if it occurs) sig­nificantly afft..·ct the motility, neural and transport functions of small howel. When the major port iun of the snrn II hnwel is trnn,plantcd, recipiem grnwth b near normal in most models (22,41 ); however, the length required to sustain the recipienr post transplant has n<ll been determined. Civen the present in­terest in triab of hl)Wcl tmnsplanuuion in humans, th is area requires further invest igat i1m.

CLINICAL EXPER IENCE All attempts at small howel t rans­

plantation in humans prior to t11l' in ­troduction l)( cyclosporine were unsucces~ful. The longest survivor lived fm 76 days; even with a human lymphncyte antigen (HLA) idenrical donor and (delayed) treatment w1th steroids, azathinprinc and antilympho­cytc glohulin, rejection and over­whelming sepsis from enteric flora pmvcd fata l (58). Other ,mempts were equally disnppointing (8,59,60). Fnl­l1iwing the success of small howcl transplantat ion using cyclosporinc in dogs and pigs, a number nf attempts at human tr,insplantation have hc:l'n

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Bowel transplantation

reported (8, Vi,61-6 3 ). The results have been poor. Typically, reiect1on 1s seen in graft hiopsics four to JO days post transplant . Rowel flu id lo:,scs increase tremendously. Stnoids and antilym­phocyte glohulm have diminished the rejection response (15.61 ), hut rejev tion has usually pr1lgressed, ncccssmu­ing graft removal around the 15th day post transplant. Pretreat ment 1if the graft with OKT3 ,int ihody has not reduced the apparent 1mmunogenic1ty uf the bowel (8,35). Rejection has oc­curred despite portal drninage of the graft, but mmt patients requiring bowel trnnsplant,nion have either a thnlm­boscd portal vein or multiple previous operations prohibiting an anastomosis to the port;il circulation (8- 10). Cyclo­sporinc regimens reported have 111-

cluded intermittent and continutius 111fus1on 05,61-63) wi th levels of cyclosporinc that are therapeutic for kidney ,111d liver transplants (200 to 400 ng/mL in who le hlmxl rad1oim ­munoaw1y 164]). Toxicity of immuno­suppression has been a common problem; cyclosporine has resulted in

ren,11 wxicny (8,6 1), while comhmed therapy (steroid, antilymphocyte glnhulin and azathioprine) has resulted in 1nfec l ious comp I icat ions ( 8, 3 5 ,62). Chi ldren receiving bowel as pan of a graft of multiple viscera have devcl­uped lymphoproliferativedisorders (65, 66). C learly, thc~e case repom Jemo11-,t n111: that, with the current ~tale of immune therapy, immune suppression following isolated ,mall bowel tran~plantation remains a difficult problem. I( a very close HLA march um be achieved, it may be po~siblc to rnntml reject inn more effect ivcly ( 58); however, th is has not hccn dcm1m­st rmed in an animal model.

As noted earlier, in considernuon nl 1hc possible advantages of porrnl drn111 -agc, l1ver trnnsph111tation reduce~ rCJl'C­tion llf co-transplanted grafts. This may he by nomclf antigen proccs~ing hy t he liver or release of soluble MHC nnti­gens wh ich then hlnck cytotoxic anti ­hlld ies 00). In cl inical t ransplantallon, improved survival of renal grafts fol ­lowing I iver transplanwt1on has bec:n dearly documented, even in the presence uf preformed antibodies to the

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graft (67) . In addition to this, anarnmi ­cf!I considerations haJ defined the con­cept of a multivisceral transplant or 'cluster operation' for combined liver and pancreaticoduodena I pathology (65,66). A complete visceral transplant - including stomach , I iver, pancreas and various lengths of bowel - can be performed for extensive celiac patho­logy. In this situation , standard immunosuppressive therapy with cycl<)sporinc, prednisone and antilym­phocyte globulin have allowed pro­lo nged survival of the associated howel (65,66) . It seemed logical co extend this to include a combined small bowel and I iver graft for short bowel syndrome with associated primary liver disease, as reported by Grant (7). Grant described a typical immunosuppressive protocol for isohned liver transplantation which has prevented rejection in the as-

ACKNOWLEDGEMENTS: Thi s wo rk was supported by the Alberta Heri tage Foundat ion for Medical Research cl inical fellowship " 12-609. The author acknnw-ledge, rhc helpful comments of Norman Kncteman, MD, Alan BR Thomson, MD, anJ Richard Fcdorn k, MD. The sccreranal a,,isrnnce ofSus:m Evarn.-Davies 1s grateful-ly apprec1mcJ .

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sociated bowel in three patients to da te (7, personal communication).

Altho ugh. initia l experience with the c luste r opera tion was entirely clini­cal and no major problem with rejec­tion of the associated bowel was reported, an experimental study in rats has shown that the cluster operation does not 'protec t' the associated bowel (68 ). However, there are no experi ­mental c.la ta dealing specifically with the issue of combined small bowel and liver transplantation. C linical success a lready achieved certainly justifies con­tinued interest in this area. Whether or not a person with short bowel syn­drome and no associated liver disease shoulc.1 receive a combined liver-small bowel graft, in hopes that the liver will reduce the immunogenicity of the bowel graft, rema ins to be seen . The survival of patients receiving an iso-

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I I. Carrel A. La rechrnquc opcmtoire des anasromoscs vascula ircs ct l;,i transplantation Jes visccrcs. Lyon Med I 902;98:859-64.

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lated liver graft for primary liver disease (over 70% fi ve year survival 169]) demonstrates that the liver transplant portion of a combinec.l liveM mall bowel transplantation would be unlike­ly to harm the recipient. Selected patients with life-threatening com­plications of short bowel syndrome and primary liver disease can ethically he considered for such therapy (70). With short howel syndrome alone (and life. threatening complications which prevent combined support with TPN), isolated small bowel transplantation could be considered (8). Given the complexities of the technical and im­muno logical aspects of the procedure, the preliminary work should he con­centrated in a few experienced centres. O ngo ing evalua tion of the results will permit an accurate assessment of the risk/benefit ratio of this procedure (70).

17. Reznick RK, Cradduck GN, Langer B, G ila, T, Cullen J B. Structure and function of , mall bowel allografts m the dog: lmmunosuppress ion wtth cyclosporin A. Can J Surg 1982;25:5 1-5.

18. Craddock GN, Nordgren SR, Remick RK, ct al. Succc,sful small b<lwel transpl:rnrauon 1n the J ng w,ing cyclosponne. T ransplantarion 1983; 35:284-8.

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24. Sigalet DL, Lees GM, Ahernc FX, ct al. The phyS1ology of adaptation 10

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n. D1ffo T, Maki T, Bal,lgh K, Mon,ic<1 bnwel tr,1mpl.mtat1.111 111 the r,tt. ca,<.'. Am J Surg 197 1; 121: 150-9. AP. (~rnft-vt·r,us-host d1,ease m fu lly T ran,pl,1111.1110n 1991; 51: 22 6. 60. Ru1: JO, L11lche1 RC lntescm.11 allllgene1c ,m,111 huwel cr,111,pl.mt.1t1on 47. lga C, (.)bpm,1 I...:, T.1kcda ) , T e:uk.1 1ran,pl.111rnt1on Am J Prm()c.:111 m the nil. T ran,pl.mtat wn 1' Pml, 1ngcd sunwa I of ,ma II 1972;2Vi79-93. 1989;47:7- 11. mti:,tmal .tllPgr,1'1 111 tht· r.11 \\'ith 61. (,uuk-1 OJ, Rc\ll111n Y, Cerf Bl'n,u.,.,,111

34. W,111,mdcr J, S...heyn1us A, LlLkgren t ytl,1,pllnne A, F1' 'i06 .md , ct .11. .;;mall 111tc,1111al G, Tufve,on C,. lmmtmo111nrph,1logy I 'i-dl·ox,,rergual111. T r.111,planr Prnc transpLmcan,m in ;i Lhild u,1ng of graft versus hmt di,easc after ,mall 1990;22: 16'i8. <.. y<.: l,isponne. T ran,plant Prnc howcl I r.m,pl,111c.1t1on 111 the rat. Stand 48. Shaffer l), Simp,1111 MA, M1lfnrJ EL, I %8:20(Suppl 3 ):288-96. J lmmunol 1990;32:9,-101. l'l ,d. Dlm,,r pretrc,11 ment wnh 62. Cohen Z, Silverman R, Levy G,

35. Grant D, S0mmcr.1ucr J, Mimcault R. monoclonal annhody for pr1.:Ycnt11111 of W.1sscfR. Langer B. Clinical ,mall et al. Treatment with conrmuou, graft-n:r,u,-ho,t d1'e.i~e follo11111g 1111t·,tmal tr,111,plantat1on w,1ng high-dose mtr,ll'cnou, qt losp, mnc ,m,111 hnwcl tr,msplantatl\m. Effect of cyclu,ponnc A .1nJ following .:lin1cal imcs1111:il dcplenon I if t-ccll suh,et,. T rnn.,plan1 merhylpredn1,olnnc. Trnnspl.,nt Proc.: trnn,pl,111tatmn. T rnmpl,mrat 11 m J'Hl<.. I 991;23:679-81 1987; 19: 2 588-90. 1989;48: 151-2. 49. Mamnell1 (;r, Knight RK, K,1pl.m S. 61. Dclt: E, Schroeder P, GunJh1ch M,

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CAN J CASTRl)l:NTEROL VOL 5 Nti 4 Jut Y/Al '( ;usT 1991

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