Transplantation of Multiple Abdominal Viscera

Original Contributions Transplantation of Multiple Abdominal Viscera

Th~mas E. Starzl, MD , PhD; Marc I. Rowe , MD; Satoru Todo, MD; Ronald Jaffe, MS, SCh; Andreas Tzakis, MD; Allen L. Hoffman, MD; Carlos Esquivel, MD, PhD; Kendrick A. Porter, MD , DSc; Raman Venkataramanan, PhD; Leonard Makowka, MD, PhD ; Rene Duquesnoy, PhD

Two children with the short-gut syndrome and secondary liver failure were oped liver failure and underwent multi treated with evisceration and transplantation en bloc of the stomach, small ple surgical procedures, including a cen intestine, colon, pancreas, and liver. The first patient died perioperatively, but tral splenorenal shunt. She was admitted to the Children's Hospital of the second lived for more than 6 months before dying of an Epstein-Barr Pittsburgh on July 29, 1983, with heart virus-associated Iymphoproliferative disorder that caused biliary obstruction failure, pulmonary edema, bilateral and lethal sepsis. There was never evidence of graft rejection or of graft-vs-host pleural effusions, anasarca, renal fail disease in the long-surviving child. The constituent organs of the homograft ure, and liver failure. Total serum bili functioned and maintained their morphological integrity throughout the 193 rubin level was 503 )J.mol/L; prothrom days of survival. bin time, 21 seconds (control, 12 (JAM A. 1989;261 : 1449-1457) seconds); and serum albumin level, 19 giL. By August 17, 1983, when a donor became available, she was anuric and receiving ventilatory assistance al IN OLDER investigations, maximum eration as shown in Fig 1 except that the though still conscious. survival after multivisceral transplan retrohepatic inferior vena cava was re The 27-month-old male donor had the tation in untreated dogs was 9 days. 1, 2 placed with the same segment from the same blood type as the recipient (A, The liver as part of the multivisceral donor. The donor organs were chilled Rh+). The graft was core-cooled with graft was rejected later and less severe with intra-aortic lactated Ringer's so chilled intra-aortic lactated Ringer's so ly than after liver transplantation alone. lution. Graft splenectomy, cyclosporine lution and removed in an adjacent oper In addition, histopathologic findings therapy (given orally or by a brief intra ating room. The cold ischemia time was suggestive of graft-vs-host disease venous course), and oral prednisone did 1 hour. There was no warm ischemia. (GVHD) were widespread by the time not have a predictable effect on the sur The organs transplanted were the same of death. 2 vival of the 22 pigs that lived through as in Fig 1 except that the kidneys were operation and for at least 2 days (Table also included with the multi visceral See also pp 1397, 1458 and 1483. 1). Diarrhea was a frequent problem. graft and connected to the recipient Eight animals developed skin lesions of bladder with ureteroneocystostomies. GVHD (Fig 2). Sepsis or GVHD usually Exsanguinating hemorrhage was con We have attempted the same opera was suspected even when the cause of tinuous throughout the recipient opera tion in two children, one of whom sur death was not obvious with gross exami tion, requiring transfusion of 61 750 mL vived for more than 6 months before nation at autopsy. Intestinal perfora of blood. When the graft was revascu dying of complications from the Iympho tion, probably secondary to rejection, larized, it had a normal appearance but proliferative disease (LPD) that is asso was found in 5 pigs. One animal that was two episodes of cardiac arrest occurred ciated with Epstein-Barr virus infec treated with a short course of cyclospor several minutes later, followed by in 3 tions. " Two other patients are known to ine lived for 104 days, had seemingly tractable hypotension that continued have had similar procedures.' normal stools, and ate well enough to until death of the patient 30 minutes gain weight from 12.5 to 30 kg. Biopsy after arrival in the intensive care unit. METHODS specimens of the jejunum, spleen, and CASE 2.-A 3112-year-old black girl Technique Standardization in Pigs liver obtained 2 months after operation underwent multi visceral transplanta Outbred Landrace pigs weighing 15 were normal. At autopsy, there was no tion at Children's Hospital of Pitts to 25 kg were anesthetized with pento grossly identifiable cause of death al burgh on November 1, 1987. Her dis barbital sodium and ketamine hydro though the clinical suspicion was of ease began with perinatal volvulus and chloride and submitted to the same op- GVHD. gangrene for which massive small-bow el resection was required with jejunoi Case Reports From the Departments of Surgery (Drs Starzl, Tod o, leal anastomosis. Liver failure second Rowe, Tzakis, Hoffman. Esquivel. and Makowka) and CASE I.-A 6JOh2-year-old white girl ary to TPN was progressive from the Pathology (Drs Jaffe and Duquesnoy) and the School of lost most of her small bowel, necessitat age of2 years. By the time oftransplan Pharmacy (Dr Venkataramanan), University of Pitts burgh Health Center, Universi ty of Pittsburgh , Pitts ing total parenteral hyperalimentation tation, the child weighed 14 kg (50th burg h, Pa ; and the Department of Pathology, St Mary's (TPN), after it had been sucked out percentile) and was 82 cm tall (fifth per Hospital and Medical School, London, Engl and (Dr while she was sitting on the drain of a centile). She had hepatosplenomegaly Porter) Reprint reque sts to Department of Surgery, 3601 Fif1h swimming pool that was being emptied. and scars from mUltiple abdominal pro Ave, Falk Ctinic. Pittsburgh, PA 1521 3 (Dr Starzl). During the following year, she devel- cedures. Total bilirubin level was 470

JAMA, March 10, 1989-VoI261, No. 10 Multivisceral Transplantation - Starzl et al 1449

Operation. - Patient 2 had removal of the liver, pancreas, spleen, distal part of the stomach, duodenum, residual small intestine, and ascending, trans verse, and descending colon. The distal sigmoid colon and rectum as well as a cuff of proximal stomach were retained. The recipient retrohepatic inferior vena cava was kept intact, and a cloaca was fashioned from the left and middle he patic veins to which the suprahepatic inferior vena cava of the multi visceral graft was anastomosed for venous out flow (Fig 1). The donor inferior vena cava was ligated below the liver. The distal graft aorta was anastomosed to the midabdominal aorta of the recipient (Fig 1). Revascularization did not cause cardiovascular instability or bleeding; most of the total operative blood loss of 5050 mL occurred during donor organ removal. Gastrogastrostomy was performed, as well as Heineke-Mikulicz pyloro plasty of the graft, to facilitate gastric emptying (Fig 1). Colocolostomy was performed. Five days later, the patient was reexplored and pinhole perfora tions were found at both the upper and lower anastomoses. The gastrogastros tomy was reinforced and left intact. Dis tally, the colonic anastomosis was con verted to an end sigmoid colostomy with suture closure of the native colon rem nant (Fig 1). Postoperative Fluid. Electrolyte, and Nutritional Management. Right-sided filling pressures and serial monitoring of urinary output and con centrations guided intravenous therapy with crystalloid and colloid in the acute postoperative setting. Thtal parenteral nutrition was used until the gastrointes tinal tract regained function. As enteral feeds were increased, the volume of TPN was reduced accordingly (Fig 3). The child could not be taught the physi Fig 1. - The recipient operation of multivisceral transplantation. Note that the venous outflow of the graft was cal act of eating. into a cloaca of the left and middle hepatic veins, leaving the recipient inferior vena cava intact. A indicates Enteral feedings were started 2 donor aorta; HA, hepatic artery; SA, splenic artery; LGA, left gastric artery; SMA, superior mesenteric artery; weeks after operation through a trans IMA, inferior mesenteric artery; and GDA, gastro-duodenal artery. nasal jejunostomy tube. Conversion to a nasogastric feeding tube was possible ~moIJL; prothrombin time, 18.2 sec studies were normal except for an eleva by the fifth week when gastric emptying onds; serum albumin level, 20 giL; and tion of total bilirubin level to 41 ~molJL had improved. Initially, feedings were aspartate aminotransferase level, 303 on the final day. Ten milligrams of continuous. As gastrointestinal tract UIL. Serum urea nitrogen, creatinine, OKT3, a mouse anti-human T-Iympho function improved, intermittent feed and serum electrolyte levels were nor cyte monoclonal antibody: was given ings were tolerated, and by day 135, mal. The hematocrit was 0.38; white intravenously 90 minutes before remov intermittent intake was used exclu blood cell count, 3800 x 1O'1L; and plate ing the graft. The graft was cooled with sively. lets, 90000 x 1O'1L. There was radiolog out preliminary warm ischemia by in In the early postoperative period, en ical evidence of pulmonary edema. fusing 500 mL of the special cold teral feedings were with simple solu preservation fluid recently developed at tions such as 5% glucose in an isotonic The Donor Operation 7 the University of Wisconsin. " It was electrolyte solution (Pedialyte) and an The donor for patient 2 was a 2- stored in an ice chest and revascularized iso-osmolar concentration of an elemen month-old white female weighing 3.25 in the recipient after 6 hours 38 minutes tal diet (Vivonex). More complex for kg who had a closed-head injury 4 days of cold ischemia. The spleen was re mulas (Portagen, Pregestimil) were not previously. Results of blood chemistry moved immediately. well tolerated. The most effective for-

1450 JAMA, March 10, 1989-VoI261, No. 10 Multivisceral Transplantation-Stafzl et al Table 1. - Fate of 22 (of 34) Pigs That Survived for at Least 2 Days After Operation ment, electrolyte management, and nutrition. Group No. of Pigs Survival, No. of Days 1 No treatment 6 5, 14, 9, 12, 10, 7 Infectious Disease 104,2,23, 16,9,9 2 Oral cyclosporine, 20 mglKg, and prednisone, 5 mg/d 6 Broad-spectrum antibiotic coverage 3 Same as group 2; graft splenectomy 5 23, 18, 7, 11, 2 14,17,3,15,14 for patient 2 was provided perioper 4 Same as group 3; 6 mglKg of cyclosporine intravenously, days 1-3 5 atively with intravenous ampicillin sodi um, cefotaxime sodium (Claforan), and metronidazole (Flagyl). Beginning on postoperative day 12, until the seventh postoperative week, selective bacterial decontamination that included oral and entel'al colistin sulfate (Polymixin E), tobramycin sulfate, and amphotericin B were given to suppress the growth of fungi and potentially pathogenic gram negative bacteria while not perturbing the growth of anaerobes.' Because the donor had positive serological test re sults for cytomegalovirus, ganciclovir was given for 14 days from the time of operation. Acyclovir (acycloguanosine) was used after the diagnosis of LPD had been established. 10

Immunosuppression Cyclosporine was given intravenous ly or enterally to patient 2 to keep the Fig 2. -Skin biopsy from a pig 14 days after multivisceraltransplantation. Note the lymphocytic infiltrate at the dermal-epidermal junction and lymphocytes in proximity to necrotic epithelial cells (satellitosis) (hematoxylin blood level at or above 1000 ng/mL by eosin, x 350). radioimmunoassay. \I When LPD was diagnosed 91 days after operation, ad ministration of cyclosporine was gradu ally discontinued and therapy was 70 stopped for 15 days. Treatment was subsequently reinstituted at low doses. The daily dosage of methylpredniso 60 lone sodium succinate (Solu-medroD was decreased from 100 to 5 mg by day 6 § 50 9. A I-week course of2.5 mg/d ofOKT3 E c- was begun on postoperative day 23 be o cause of the suspicion of rejection. Nine .~ 40 C doses of25 mg of azathioprine were giv Q) en intravenously for a I3-day period be .~

134 136 138 140 142 144 146 148 Pharmacokinetic Studies Days After Operation Patient 2 was given 50 and 38 mg of intravenous cyclosporine for a 2-hour period on postoperative days 74 and Fig 3. - Enteral and parenteral alimentation. As a blenderized diet was increased, we were able to gradually reduce total parental hyperalimentation (TPN) to a very low level. 102, respectively. This was followed the next day (postoperative days 75 and 103, respectively) with oral doses of 550 mula appeared to be an iso-osmolar ele bile-salt binding agent, cholestyramine, and 150 mg in olive oil. Multiple blood mental diet (Peptamen) containing pep were added at various times to slow the samples were drawn on these study tides as the protein source and only a transit time and improve fluid ab dates and analyzed for cyclosporine con small amount of long-chain triglycer sorption. centration by high-perfonnance liquid ides, which allowed TPN to be gradually Qualitative and quantitative mea chromatography. 12 reduced. Shortly thereafter, it was pos surements of intravenous and enteral sible to give a blenderized diet contain infusates as well as output of urine, Assessment of Graft Function ing Peptamen, meats, and vegetables stool, and catheter drainage (gastric, Liver. - Findings from conventional and to progressively wean her from biliary, and Jackson-Pratt) were done. hepatic function tests were obtained al TPN (Fig 3). Bulk fiber in the fonn of Daily weights were taken. These data most daily and correlated with the re pectin or psyllium complexes and the were used to guide volume replace- sults of tests on liver biopsy samples.

JAMA, March 10, 1989-Vo1261, No. 10 Multivisceral Transplantation-Starzl et al 1451 Intestine. -Absorption was estimat human serum albumin labeled with 25 ed from serum glucose levels after Pep mCi of chromium 51 and by monitoring tamen administration and by cyclospor the amount of isotope that appeared in ine blood levels after gastric instillation the stool during the next 4 days (normal of this drug. The percentage ofnasogas ly < 0.5% for a 3-day period).'3 Stool tric fluid absorbed was determined by electrolytes, glucose, and protein levels measuring stool output. Albumin leak were measured. age through the intestinal mucosa was Pancreas. - Serial serum trypsin and studied in the fourth postoperative amylase levels were obtained. Serum C month after the intravenous injection of peptide levels were measured and com-

Fig 5. -Computed tomographic scans of initiallym phoproliferative disease process. Top, One hun· dred nine days after transplantation . Multiple lucen cies within the liver parenchyma are seen. Histological examination of the cells obtained on liver biopsy revealed a polyclonal Iymphoprolifera tive disorder (see Fig 6, right). Bottom, One hundred thirty-seven days after transplantation. Calcific rims Fig 4.-Demonstration of OKT3. Left, A small mesenteric donor lymph node is embedded in fat (frozen surround many of the parenchymallucencies. Histo section, pinocyanol. X II 0). Right, Some cells in the nodal sinuses, cortex, and paracortex (arrows) stain logical examination revealed necrotic Iymphoproli darkly for the presence of murine IgG (alkaline phosphatase/antialkaline phosphatase, x 110). ferative cells (see Fig 6, center).

Fig 6. -Allograft liver, Iymphoproliferative disease. Left, Allograft liver biopsy specimen at 3 months. A diHuse plasmacy toid lymphoid proliferation destroys hepatic tissue (Giemsa, x 220). Center, Allograft liver biopsy specimen at 3 'I. months. Necrotic Iymphoproliferative disease is represented by ghost cells that have lost both nuclear and cytoplasmic staining detail. Occasional nucleated inflammatory cells persist (hematoxylin-eosin, x 240). Right, Hepatic hilar vasculi tis present at autopsy. Branches of the hepatic artery, the hilar fibrous tissue, head of pancreas, and adjacent colon are permeated by a very polymorphous, anaplastic-looking infiltrate quite diHerent from the earlier Iymphoproliferative disorder (hematoxylin-eosin, x 440).

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1452 JAMA, March 10, 1989-Vol 261, No. 10 Mullivis ceral Transplantation-Starzl et al 855 c 15 ~ 684 ~ 0 iIi E 510 E ::I.. 221 OJ OJ 342 (f) > OJ

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Fig 8. - Parallel graphs of serum total bilirubin levels and cyclosporine (radioimmunoassay IRIA]) levels. Four major findings: (1) Rapid fall in total bilirubin level immediately after transplantation. (2) Progressive rise in bilirubin level from days 7 to 30. OKT3 administered for one week beginning day 23 with a decline to normal after treatment. (3) No rise in bilirubin level is seen during the early Iymphproliferative disease (day 91). Cyclosporine was subsequently stopped but restarted due to fear of potential rejection or graft-vs-host disease. (4) Late. rapid rise of bilirubin level caused by the obstructing. fatallymphoproliferative disease that Fig 7.-Computed tomographic scan and cholan was only tranSiently relieved by biliary catheter drainage. giogram of terminal Iymphoproliferative disease process and the hemisected liver at autopsy. Top. Computed tomographic scan at 165 days. The he patic ducts are obstructed by a large hilar mass Special Pathological Studies weeks after transplantation. At autop sy, the depletion of lymphoid tissue discovered on histological examination to be mor In addition to routine histopathologic phologically different than the previous Iymphoproli from the grafted viscera was remark ferative disease process (see Fig 6. right). This was processing, portions of all biopsy sam able, and, in addition, small nodes from confirmed by transhepatic cholangiogram (center). ples were snap frozen to immunostain Note the resolving Iymphoproliferative disease in the donor mesentery and the host's per for lymphocyte markers and other stud iaortic region were depleted of lympho the periphery of the liver on the computed tomo ies. Monoclonal antibodies to HLA-DR, graphic scan. Bottom. Transected liver at autopsy cytes. The effect, if any, of graft irradia confirms previously mentioned findings and reveals CD2, CD3, CD4, CD8, CD20, M02, and tion after transplantation was not widespread parenchymal necrosis with hemor K and A light chains were used. Poly rhage. Note catheters within the hepatic ducts. analyzable. clonal antibodies to IgA, IgG, IgM, ('t antichymotrypsin, lysozyme, and S100 protein were also used. For special typ Survival and Causes of Death ing studies in tissues, the monoclonal antibodies used had specificity against Patient 1 died 30 minutes after arrival pared with the levels of 0.24 to 0.72 in the intensive care unit. The graft in pmollmL obtained in 20 nonfasting HLA-A3 and Bw4; they were detected with an alkaline phosphatase/antialka patient 1 had nonspecific findings of ter diabetics. minal shock. At autopsy, the heart had line phosphatase reaction. 14 biventricular hypertrophy and intersti Histocompatibility (HLA) Typing RESULTS tial myocarditis with focal fibrosis and With lymphocytotoxicity and two adjacent chronic pericarditis. The lungs color fluorescence testing, patient 2 Localization of OKT3 From Donor had massive and multiple pulmonary showed the following phenotype: Before Treatment emboli as well as severe congestion with HLA - A3,30;B35,w42(Bw6);DRw6, - The donor lymph nodes sampled 1 focal hemorrhages and necrotizing vas (DRw52);DQwl,w3. Because the graft hour after the intravenous administra culitis. The kidneys had acute bilateral was flushed with OKT3 monoclonal tion of 10 mg of OKT3 had a heavy con tubular necrosis. antibody, donor lymphocytes could not centration of mouse immunoglobulin Patient 2 lived for 192 days after be readily HLA typed because of high (Fig 4). The murine globulin was not transplantation; 143 days were spent on background lymphocytotoxicity. How sought in extranodal donor tissues. the ward and 49 days in the pediatric ever, AI, A26, and probably Bw4 were Graft-vs-host disease was not ob intensive care unit. Multifocal LPD was identified. The recipient had cytotoxic served in specimens of the recipient co diagnosed by computed tomographic antibodies against only 2% of the human lon during life or at autopsy, or in the scan on postoperative day 91 (Figs 5, population. skin biopsy sample of a transient rash 3 top, and 6, top). One month earlier on

JAMA. March 10. 1989-VoI261. No. 10 Multivisceral Tran splantation -Starzl et al 1453 January 5, 1988, the Epstein-Barr pro file had shown IgG viral capsid antigen to be positive at a 1:160 titer, up from 1:5 on December 24, 1987. The IgM viral capsid antigen, IgG (EA, D, R), and anti-Epstein-Barr nuclear antigen were all less than 1:5 on February 22. When a biopsy of the hepatic LPD le sions was done at 3 months, the cells tested positive for HLA-A3 but not for Bw4, consistent with recipient but not with donor origin of the lymphoid cells in the biopsy specimen. Kupffer's cells in adjacent uninvolved liver had the same recipient HLA antigens. This was not surprising since Kupffer's cells are known to be replaced with recipient macrophages within 100 days. " The plasmacytoid cells in the Iymphoproli Fig 9.-Allograft liver. Left, Biopsy specimen obtained on day 11 after transplantation reveals a cholangitis feration had cytoplasmic immunoglobu and pericholangitis. Neutrophils are present in and around a bile duct (B). Right, Allograft liver biopsy lin; K and A. chains were equally repre specimen obtained at 6 months. The liver has canalicular cholestasis, bile ductular proliferation, and a sented but virtually all cells had IgG generalized fine sinusoidal fibrosis (8) believed to be most consistent with prolonged hyperalimentation eHect heavy chain. These findings were sug (hematoxylin-eosin, x 200). gestive of polyclonality.3.4 Anti-Ep stein-Barr nuclear antigen was detect ed in the lymphoid cells and the presence of Epstein-Barr virus DNA was confirmed using a DN A probe. When immunosuppression was stop ped on day 104 for 15 days, the lesions underwent total necrosis during the next 31/2 weeks as proved by biopsy specimens. By day 130, there was calci fication in the rims of the hepatic masses (Figs 5, bottom, and 6, center). Howev er, by day 165 a new hilar mass had appeared, causing an obstruction of the bile duct (Figs 6, right, and 7). The ob struction was partly relieved with cath eter drainage but sepsis, cardiovascular collapse, and multiple system organ fail ure eventually followed . At autopsy, the liver had multiple ne crotic nodules of ''burned out" polymor phous LPD with calcific periphel;es. The new hilar LPD lesion was morpho logically very different from the earlier ones. This lesion also involved acontigu Fig 10.-Barium meal-day 109. Note the feathery normal appearance of the small intestine mucosa. ous segment of the colon wall and the head ofthe pancreas. The cells had large bizarre nuclei and surrounded larger Organ Function and Structure minases rose during a 10-day period blood vessels, often infiltrating and de from 11 /2 to 30 times normal, reaching a stroying the muscular walls of the hilar Liver. - Within 48 hours of trans peak aspartate aminotransferase value arteries. The cells, unlike those of the plantation, the bilirubin level fell from of 1473 UlL. At the same time, there earlier LPD, were not plasmacytoid. 564.3 to 130 fJ-moVL. After this, there was little effect on the bilirubin level. It Findings of typing for Band T lympho was an insidious rise in bilirubin level, was thought that the necrosis had oc cytes and monocyte-dendritic cells were which did not respond to pulse steroid curred very abruptly. negative. There was destructive hilar therapy (Fig 8). The I-week course of Normal or near-normal prothrombin vasculitis with left and right hepatic OKT3 beginning on postoperative day times suggested intact synthetic func duct infarction and bacterial over 23 did not influence the bilirubin level, tion. Serum albumin concentrations growth. Hepatic parenchymal infarc but just after this, the levels began to were well maintained until a short time tion was widespread. Sinusoidal fibrosis fall. A final increase in bilirubin level before death. and ductular proliferation consistent was due to an obstruction of the bile Fifteen sequential liver biopsy speci with hyperalimentation effect was duct by the LPD. mens were examined. Purulent cholan also noted. Early transaminase level rises to a gitis was diagnosed on day 11, with Two small perforations of the intes peak of323 UlL returned to normal by 1 gram-negative bacilli identified in the tine found at autopsy were additional week. During the time of withdrawal of tissue. Progressive cholestasis, bile foci of potentially lethal sepsis; one was immunosuppression and necrosis of the ductular proliferation, hepatocyte bal recent and the other was walled off. lymphoma, the levels of serum transa- looning, and sinusidal fibrosis were be-

1454 JAMA. March 10. 1989-VoI261 , No. 10 Multivi sc eral Transplantation-Starzl et al tion was determined to be very effi cient, as only small amounts of reducing sugars were noted in the stool during Peptamen administration. The amount of intravenous hyperalimentation was greatly reduced and nearly stopped when nasogastric feedings were in creased with both Peptamen and blen derized diets (Fig 3). Positive nitrogen balance was present on days 4 to 17. Immediately after operation, the pa tient weighed 12.6 kg. This increased to 15.6 kg at the time of nasogastric feed ings. Her weight reached a maximum of 16.3 kg 3 months postoperatively. How ever, it dropped to 14.5 to 15.0 kg in the last month of life. The allografted large bowel was sam pled at 6 days, 3 months, and 6 months after transplantation. No suggestion of rejection was observed (Fig 11, top left). The epithelium was intact and there was a paucity oflymphoid tissue in the 6-month biopsy specimen. At autopsy, the allografted gastric mucosa was mildly atrophic when com pared with the remnant of host stomach (Fig 11, top right). The small intestine had intermixed wnes of atrophic and hypertrophic mucosa. The submucosa was mildly fibrotic and the intestinal arteries were thick walled. There was no evidence of lymphangiectasia (Fig 11, bottom left). No solitary lymphoid follicles were visualized in the large in testine. Peyer's patches were not seen in the ileum nor were there plasma cells. Pancreas. -Serum amylase levels were less than 42 U/L throughout the entire course. Ten weeks after opera tion at a time when the child was not being administered exogenous pancre atic enzymes, trypsin activity was de Fig 11. - Gastrointestinal tract. Top left, Colonic biopsy specimen from the donor colon proximal to the tected in the colostomy drainage be colostomy, taken 1 week before death (6 months after transplant). The glands eX1end to the muscularis yond a 1:256 dilution (normal for this mucosae, a normal finding, and there is neither cellular infiltration nor epithelial damage. Lymphoid tissue is sparse (hematoxylin-eosin, x 280). Top right, Donor stomach at autopsy. The mucosa has mild atrophy and age, > 1:40). The findings were consis some fibrosis of the lamina propria (hematoxylin-eosin, xI80). Bottom left, Donor ileum at autopsy. In places, tent with normal proteolytic activity in the villous architecture reveals hyperplasia rather than atrophy. The surface epithelium is intact, the lamina the feces. propria somewhat fibrotic, but there is no cellular infiltrate (hematoxylin-eosin, x 150) Bottom right, Donor Serum C peptide level was 0.72 pancreas at autopsy. There are foci of cystic ductular proliferation in the head of the pancreas. For the most part, islets are abundant (arrows) and there is little atrophy, interstital fibrosis or cellular infiltrate (hematoxylin pmol/mL on day 37. The level was 2.16 eosin, x 180). pmol/mL on day 93, three times higher than the upper limit of the nonfasting lieved to be evidence of hyperalimenta creted into the stool over a 4-day period. diabetic. tion-induced damage (Fig 9). Features At the end of the second month , only At autopsy, the transplanted pancre of rejection were never observed in the 5.0±7.0 (SD) giL of total protein, as was nearly annular and appeared vir liver biopsy specimens. The autopsy 33.36 ± 25.37 (SD) fJ..mol/L of glucose, tually normal except for minor ductoin findings reflected damage secondary to and low concentrations of sodium and sular proliferation with microcystic the LPD. potassium were detected in the stool. changes (Fig 11, bottom right). The Hollow Viscera.-An upper This suggested that the stool losses gastrointestinal tract series with a were mainly water. Two months after Cyclosporine Pharmacokinetics small-bowel follow-through was done transplantation, stool volume became The clearance of cyclosporine follow by administering a barium meal on day less and the percent fluid absorption im ing intravenous administration was 3.4 109 (Fig 10). Transit time from stomach proved from a low of about 10% to a high mLimin per kllogram during the first to colon was 2 liz hours, which is normal of approximately 75%. The majority of study period (postoperative days 74 and for a child of this age. The mucosal stool output was between midnight and 75) and 3.8 mLimin per kllogram during pattern was normal (Fig 10). The muco 7 AM. Thtal stool output during periods the second study period (postoperative sal barrier was intact. In the fourth of fasting (156 ± 24 [SD] mL/24 h) was days 102 and 103). The half-life of cyclo postoperative month, only 0.46% of the similar to that during feeding (159 ± 145 sporine was 1l.3 and 16 hours for the intravenous 5lC-labeled albumin was ex- [SD] mLl24 h). Carbohydrate absorp- respective periods. Oral bioavailability

JAMA. March 10, 1989 - Vol 261 , No.1 0 Multivisceral Transplantation-Starzl et al 1455 Table 2.-Cyclosporine Pharmacokinetics in untreated and immunosuppressed dogs" '-"" and studied decisively by Mon Volume Cyclosporine Clearance Rate, of Distribution, chik and Russell3

1456 JAMA March 10. 1989-Vol 261. No . 10 Multivisceral Transplantation-Starzl et al lymphoid tissue in the graft will simplify 29961 from the National Institutes of Health, Be Belzer FO. Lethal graft versus host disease in a or complicate the task. Recent studies thesda, Md; and the Pathology Education and Re recipient of a pancreas-spleen transplant. Trans search Foundation of Pittsburgh, Pittsburgh, Pa. plantation. 1986 ;41:544-546 . with bone marrow by Knobloch and Antibodies were purchased from Beckton Dick 21. Craddock GN , Nordgren SR, Reznick RK, et Dennert39 have suggested that the inson, Mountain View, Calif, and from Dako Corp, al. Small bowel transplantation in the dog using immunologically active T lymphocytes Santa Barbara, Calif. Monoclonal antibodies to cyclosporine. Transptantation. 1983;35:284-288. responsible for GVHD could also be in HLA specificities were generously supplied by 22. Diliz-Perez HS, McClure J, BedeW C, et al. Karin Nelson, PhD, Genetic Systems, Seattle, Successful small bowel allotransplantation in dogs trinsically immunosuppressive and nec Wash. with cyclosporine and prednisone. Transplanta essary for graft acceptance provided References tion. 1984; 37:126-129. 23. Ricour C, Revillion Y Arnaud-Battandier F they are present in appropriate num 1. Starzl TE, Kaupp HA Jr. Mass homotransplan et al. Successful small bo;"'el allografts in piglet bers. tation of abdominal organs in dogs. Surg Forum. 1960;11:28-30. using cyc1osporine. Transplant Proc. 198.3; 15 The most encouraging observation in (suppll):3019-3026. 2. Starzl TE, Kaupp HA Jr, Brock DR, Butz GW our patient was that unequivocal func Jr, Linman JW. Homotransplantation of mUltiple 24. Grant D, Duff J, Zhong R, et a!. Successful intestinal transplantation in pigs treated with cy tion was obtained from all of the organs visceral organs. Am J Surg. 1962;103:219-229. c1osporine. Transplantation. 1988;45:279-284 . in the multi visceral graft. Despite early 3. Starzl TE, Nalesnik MA, Porter KA, et al. Re 25. Kirkman RL, Lear PA, MadaraJL, Tilney NL. involvement with cholangitis and later versibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid thera Small intestine transplantation in the rat: immunol with LPD and biliary obstruction, the ogy and function . Snrg&ry. 1984 ;96:280-287. py. Lancet. 1984;1:583-587. liver provided good synthetic and other 4. Nalesnik MA , Makowka L, Starzl TE. Thediag 26. Hatcher PA , Deaton DH, Bollinger R. Trans function for more than a half year. The nosis and treatment of post-transplant lymphopro plantation of the entire small intestine in inbred rats using cyc1osporine. Transplantation. hollow gastrointestinal tract viscera al liferative disorders. Curr Probl Surg. 1988;25:365- 472. 1987;43:478-484. lowed near-total enteral nutrition for 5. Williams JW, Sankary H N, Foster PF, Lowe J, 27. Lee KKW, Schraut WHo Structure and func extended periods. Pancreatic function Goldman GM. Splanchnic transplantation: an ap tion of orthotopic small bowel allografts in rats was present even though exogenous in proach to the infant dependent on parenteral nutri treated with cyclosporine. Am J Surg. 1986; 151:55- tion who develops irreversible liver disease. 60. sulin was intermittently given with 28 .. Lillehei RC, Goott B, Miller FA. The physio JAMA. 1989;261:1458-1462. TPN. None of the organs ever had histo 6. Cosimi A, Colvin R, Burton R, et a!. Use of log'lc response .of the small bowel of the dog to pathologic evidence of rejection. monoclonal antibodies to Tcell subsets for immuno IschemIa Includmg prolonged in vitro preservation Much was learned about the manage logic monitoring and treatment in recipients of re of the bowel with successful replacement and sur vival. Ann Snrg. 1959;150:543-560. ment of the infectious problems that nal allografts. N Engl J Med. 1981 ;305:308. 7. Jamieson NV, Sundberg R, Lindell S, et a!. 29. Lillehei RC, Longerbeam JK, Goott B, Gold have plagued efforts at transplantation Successful 24 hour liver preservation: a preliminary berg S, Scott WR. Gastrointestinal transplanta tion. Surg Clin North Am. 1962;42:1197-1218. of the gastrointestinal tract organs. It report. Transplant Proc. 1988;20:945-947. has been recognized for 30 years that 8. Wahlberg JA, Love R, Landgaard L, Southard 30. Monchik GJ, Russell PS. Transplantation of JH, Belzer FO. Seventy-two hour preservation of the small bowel in the rat: technical and immunolog bacteria indigenous to the gastrointesti ic considerations. Surgery. 1971 ;70:693-702. the canine pancreas. Transplantation. 1987;43:5-8. nal tract translocated after hepatic 9. Stoutenbeek CP, van Saene HKF, Miranda DR, 31. Cohen Z, MacGregor AB , Moore KTH, Falk transplantation when the grafts were Zandstra DF, Binnendijk B. The effect of oral non RE, Langer B, Cullen JB. Canine small bowel 4o 41 transplantation: a study of immunologic responses. damaged by ischemia or rejection. . absorbable antibiotics on the emergence of resis Arch Surg. 1976;111:248-253. The problem is undoubtedly even more tant bacteria in patients in an intensive care unit. J Antimic1'Ob Clwmotlwr. 1987;19:513-520. 32. Williams JW, McClellan T, Peters TG, et a!. critical following preservation and 10. Hanto DW, Frizzera G, Gajl-Peczalska KJ, et Effect of pretransplant graft irradiation on canine transplantation of the small intestine.42 a!. Epstein-Ban- virus induced B-cell lymphoma intestinal transplantation. Surg Gynecol Obstet. 1988;167: 197-204. "Selective decontamination" was at after renal transplantation. N Engl J Med. 33. Deitz E , Ulrich K, Schach T, et al. Graft-ver tempted in our patient with nonabsorb 1982;306:913-918. 11. Donatsch P, Abisch E, Hornberger M, Trabar sus-host reaction in small bowel transplantation J able antibiotics,9 hoping to prevent the R, Trapp M, Voges R. A radioimmunoassay to and possibilities for its circumvention. Am Surg. 1986;151 :379-386. overgrowth and "leak" of pathogenic measure cyclosporin A in plasma and serum sam 34. Lee KKW, Schraut WHo In vitro allograft irra gram-negative microorganisms and of ples. J Immunoassay. 1981;2:19-32. 12. Sawchuk RJ, Cartier LL. Liquid chromato diation prevents graft versus host disease in small Candida while preserving a normal flo bowel transplantation. J Surg Res. 1985'88:364- graphic determination of cyclosporin A in blood and 372. ' ra of intestinal anaerobes. The effort plasma. Clin Clwm. 1981;27:1368-1371. . 35. Deitz E, Muller-Hermelink HK Ulrich K was successful in that gram-negative 13. Waldmann TA.. Gastrointestinal protein loss Thiede A, Muller-Ruchholtz W. of bacteria were never again cultured demonstrated by olCr labelled albumin. Lancet. Dev~lopment graft versus host reaction in various target organs from the blood, although Candida was 1961;2:121-123. 14. CordellJL, Falini B, Erben WN, eta!. Immun after small intestinal transplantation. Transplant not eliminated. Subsequent bacter oenzymatic labeltingofmonoclonal antibodies using Proc.1981;13:1215-1216. emias were with gram-positive cocci Immune complexes of alkaline phosphatase and 36. Shaffer D, Maki T, DeMichele SJ, eta!. Studies predominantly staphylococci, that could monoclonal anti-alkaline phosphatase (AP-APP in small bowel transplantation: prevention of graft versu.s host disease with preservation of allograft be controlled with appropriate antibiot complexes). J Histoclwm Cytochem. 1984;32:219- 229. functIOn by donor pretreatment with antilympho ics or venous catheter removal. The mi 15. Kashiwagi N, Porter KA, Penn I Brettsch cyte serum. Transplantation. 1988;45:262-269. croorganisms in the blood usually could neider L, Stanl TE. Studies of homogr~ft sex and 37. Starzl TE. Experience in RenalTransplanta be predicted 1 or 2 days in advance by of gamma globulin phenotypes after orthotopic ho tion. Philadelphia, Pa: WE Saunders Co; 1964:164- 170. motransplantation of the human liver. Surg finding the same bacteria in the stool. 38. Starzl TE (with the assistance of Putnam CW). Forum. 1969;20:374-376. The most important conclusion from 16. Ramsey G, Nusbacher J, Starzl TE, Lindsay Experience in Hepatic Transptantation. Philadel our longest surviving patient was that GD. Isohemagglutinins of graft origin after ABO phia, Pa: WB Saunders Co; 1969:203-206,227-233. she came tantalizingly close to truly unmatched liver transplantation. N Engl J Med. 39 .. Knobloch C, Dennert G. Loss of Fl hybrid resIstance to bone man-ow grafts after injection of long-term survival with a functioning 1984;311:1167-1170. 17. BurdickJF, Vogelsang GB, Smith WJ, Farmer parenteral lymphocytes. Transplantation. 1988; gastrointestinal tract. There were no ER. Severe graft-versus-host disease in a liver 45:175-183. 40. Brettschneider L, Thny JL, Boose DS, et a!. mortality factors that were beyond ra transplant recipient. N Engl J Med. 1988;318:689- Specific bacteriologic problems after orthotopic liv tional explanation nor any management 691. 18. Stanl TE, Iwatsuki S, Shaw BW Jr, et a!. er transplantation in dogs and pigs. Arch Surg. adjustments that require therapeutic 1968;97:313-322. Pancreaticoduodenal transplantation in humans. 41. Starzl TE (with the assistance of Putnam CW). tools that are not now available. It Surg Gynecol Obstet. 1984;159:265-272. seems inevitable that further cautious 19. Gonwa TA, Goeken NE, Schulak JA, Nghiem Experience in Hepatic Transplantation. Philadel phia, Pa: WB Saunders Co; 1969:322-347. DD, Corry RJ. Failure of cyclosporine to prevent trials of multivisceral and/or intestinal 42. Thledo-Pereyra LH, Raij L, Simmons RL Na in vivo T cell priming in man: studies in allogeneic transplantation will be made. jarian JS. Role of endotoxin and bacteria in' long spleen transplantation. Transplantation. 1985; term survival of preserved small bowel allografts. This study was supported by research grants 40:299-304. Surgery. 1974 ;73:474-481. from the Veterans Administration; grant AM- 20. Deierhoi MH, Sollinger HW, Bozdech MJ,

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