GARTNER, JC

IWATSUKI, S

MALATACK, JJ

SHAW, BW

STARZL, TE

ZITELLI, BJ

English

PubMed

Zitelli, BJ

Gartner Jr, JC

Malatack, JJ

Shaw Jr, BW

Iwatsuki, S

Starzl, TE

Name not available

Hepatic homograft survival in pediatric orthotopic liver transplantation with cyclosporine and steroids

D-Scholarship@Pitt

Hepatic Homograft Survival in Pediatric Orthotopic Liver Transplantation with Cyclosporine and Steroids B. J. Zitelli, J. C. Gartner, Jr., J. J. Malatack, B. W. Shaw, Jr., S. Iwatsuki, and T. E. Starzl CYCLOSPORINE (CsA) used with ste-roids has been a major influence in the improved survival of patients undergoing orthotopic liver transplantation. The overall results of patient survival have been published elsewhere. I •2 Part of the increased survival rate is dependent on retransplantation for homograft failure. We report our experience of patient and homograft survival as well as major causes for graft failure. MATERIALS AND METHODS From May II. 1981. to March 7. 1983.43 patients ranging in age from 7'/2 months to 18 years received 57 orthotopic liver homografts. Table I lists the indications for transplantation. Patients reported here have been assigned OT (orthotopic transplant) numbers. which allows one to follow and compare the course of anyone patient in previous or subsequent publications. Details of patient selection and immunosuppression have been described in detail e1sewhere.'-J Briefly. patients were given oral CsA (17.5 mgjkg) or an intravenous infusion of CsA (5 mgjkg) a few hours preoperatively. Intrave-nous CsA was continued at 5 mg/kgjday. divided twice daily. until oral CsA could be begun at 17.5 mg/kgjday. divided twice daily. Most pediatric patients were given a burst of steroids beginning the day of surgery (100 mg methylprednisolone) and rapidly tapered to a baseline dose (20 mgjday of prednisone) 4-5 days postoperatively. This baseline steroid dose was further decreased pending the patient's clinical course. If clinical signs of rejection appeared. the immunosup-pression regimen was modified. Initially. a single bolus of hydrocortisone (500-1000 mg) was given intravenously. If the patient showed only moderate improvement, a cycle of prednisone similar to that given immediately postoper-atively was also begun. In addition. CsA doses were occasionally increased. monitoring clinical and laboratory evidence for nephrotoxicity. Whole blood CsA levels were From the University of Pittsburgh Health Center and School of Medicine. Children's Hospital of Pittsburgh. Pittsburgh. P A. Reprint requests should be addressed to B. J. Zite//i, Children's Hospital of PillSburgh. 125 DeSoto Street. Pittsburgh. PA 15213. @ 1983 by Grune & Stratton. Inc. 0041-1345/83/1505-0073$01.00/0 measured by high-pressure liquid chromatography' in patients transplanted since January 1983. and CsA doses were adjusted to achieve trough levels of 100-400 ngjml. Graft failures occurred when irreversible and pro-gressive hepatic injury was noted by increases in bilirubin and hepatocellular and canalicular enzymes as well as' worsening prothrombin time. RESULTS AND DISCUSSION From 5/ II /81 to 3/7/83. 43 pediatric" patients received 57 hepatic homografts. Overall patient survival to 3/7/83 is 63% (27/43). Thirteen patients (30%) received. multiple transplants; 12 patients received two homografts. and I patient received three homografts. The overall patient survival of retransplanted patient is 38% (5/13). • Twenty-four overt graft failures occurred in the 57 homografts (42%). Of the 16 patients who died. transplantation in 6 patients took. place while the patient was moribund, and the ' patient expired shortly after surgery. Graft I function was assessed shortly prior to death. I Those six grafts are not included in graft«: failures. Causes of graft failure and contributing causes of graft failure are listed in Table 2. Although the primary cause of graft failure is given, other factors often contributed to graft injury. At times it was difficult to determine which was the dominant factor responsible graft failure. The most prominent patholog- . ical event found in the graft at retransplanta-tion or autopsy helped determine the major factor. Infarction, rejection, vascular acci-dents, and infection were the major causes of -graft failures (Table 3). Infarction Hepatic infarction accounted for the loss of eight grafts (33%). All but two of these grafts never had adequate function and were rna by an immediate and continued postoperative enzyme elevation, often in the thousands. Bili-2592 Transplantation Proceedings, Vol. XV, No.4, Suppl. 1 (December). 1983 GRAFT SURVIVAL WITH CYCLOSPORINE Indications for Pediatric Liver Transplantation Biliary atresia 18 Metabolic Alpha-l-antltrypsin deficiency 7 Glycogen storage Disease I Hereditary tyrosinemia 1 Wilson's disease 2 Sea blue histiocyte Biliary hypoplasia 4 Chronic active hepatitis 3 Familial cholestaSis 3 Neonatal hepatitis Biliary obstruction Benign liver tumor 1 Total 43 'rubin also rose, and clotting studies worsened. Death occurred if retransplantation did not within 72-96 hr. Reasons for graft infarction were not clear because vessels were "all patent at retransplantation or autopsy. Possible factors for infarction might include of an already injured graft or damage to the graft during harvesting, trans-port, or implantation. An example of the latter might be OT 279B. who suffered an intra-operative cardiac arrest. The graft never func-tioned well. Two patients, OT 232 and OT 240, had a onset of massive hepatic infarction. OT 232 had an absent inferior vena cava. Each had initial good function postoperatively but suffered subsequent fulminant hepatic . and death at 12 and 10 days, respec-tively. Both grafts had patent vascular anasto-i moses at postmortem examination. Both 1IIPatiems, however. had preformed T-cell warm antibodies directed against the graft. Whether acute rejection was contributory to the infarc-tion is purely speculative. ... Table 3. Status of SUPViving Grafts Discharged survivors· 26 Bilirubin < 1.5 mg/dl 24 SOOT < 100lU 25 Status Well Chronic rejection Mild rejection 24 2593 ·OT 246, not included. recently underwent a third trans-plant and is still hospitalized. Rejection Rejection occurred as a major cause of graft failure in 29% (7/24) of grafts. In addition, it was a contributing factor in the failure of another 4 grafts. Pathological fea-tures of rejection have been described else-where.s-7 In most cases, rejection was mani-fested by fever, malaise. hepatomegaly with induration of the graft. ascites. and vague abdominal discomfort. Bilirubin increased and canalicular enzymes increased. usually out of proportion to the hepatocellular enzymes. Generally an ominous prognostic feature has been the disappearance of bile ducts within the portal triadsY Clinically, rejection mimicked other disorders, especially biliary tract obstruction and portal vein occlu-sion. If the patient did not respond to specific therapy directed toward rejection. the patho-logical process could be determined with cer-tainty only with specific investigations such as cholangiography and angiography, as well as biopsy. In addition, these clinical entities may not be exclusive of each other. and it is at least theoretically possible that they may contrib-ute to one another. Such an example might be decreased hepatic blood flow during rejection Table 2. Causes of Graft Failure Failure (No.1 (N - 241 Major Cause Contributing Cause .0-----------------------------------------------------------------------------Hepatic infarction (8) Rejection (7) -Vascular accident (51 Infection (4) • OT 265. 271A. 271B. 240. 232.284A. 203A, 279B OT 216. 214A, 203B. 266A. 229A. 246A. 2S0A OT 220. 259A. 273A, 267. 214B OT 201.191,2598. 279A OT 232. 214B. 240.191 OT 232. 259B. 266A OT 259A, 266A. 246A 2594 causing vascular thrombosis and/or infec-tion.8 OT 266A had clinical and pathological evidence for chronic rejection while on 18 mg/kg/day of CsA. Prior to retransplanta-tion, CsA kinetics studies demonstrated poor oral absorption at that dose. Retransplanta-tion occurred 57 days after the initial trans-plant. Pathology of the initial graft demon-strated severe rejection and a branch hepatic artery thrombosis. Cyclosporine was in-creased to 29 mg/kg/day, achieving adequate blood CsA levels, possibly preserving good function of the second graft. No nephrotoxic-ity was noted. This patient demonstrated the possible interplay of several pathological pro-ZITELLI ET AL cesses as well as the possible potential value o. measuring CsA levels. In addition, this patien: was representative of many of our patient~ who received higher than the standard CsA dose and appeared to tolerate it without overt nephrotoxicity. Vascular Accidents Vascular complications accounted for thl loss of 5 (21 %) grafts. OT 220A had no portai vein found at transplant, and the portal anas-tomosis was made to the recipient's vena cava. The graft failed from portoprival flow. OT 259A suffered both portal vein thrombosis and hepatic artery thrombosis; OT 267 throm-bosed the hepatic artery; OT 273A had a OT :: 214 2 ~ yo. male -,.., CTA 1-.1 GS\"P •• SlOT .. IIU .. 'd' 100 eo 10 40 zo 0 100 zoo IV ... c • • a. .. DAYS MONTHS DAYS Fig. 1. Clinical course of OT 214. Note the late onset of rejection marked by rises in SGOT, GGTP, and Rejection persisted despite aggressive immunosuppression, culminating in ratransplantation on day 241. course of the second transplant was marked by rises in the ume laboratory studies. Steroid boluses did not alter the course. Postmortem examination confirmed the premortem diagnosis of portal vein thrombosis. Vertical bars during steroid therapy indicate large boluses of i.v. steroid. The CsA graph indicatesl.v. dosing by the solid bar and oral dosing by the open bar. GRAFT SURVIVAL WITH CYCLOSPORINE U1Il1UU""" of the portal vein and inferior vena and OT 214B had a thrombosed portal ...... sf~1aK Vascular complications may have been in the failure of another 3 cases. The course of OT 214A and B is depicted in 1. The first graft was lost to rejection, and second to a portal vein thrombosis. This was unusual because unrelenting "re:ie(:ticm occurred several weeks after achiev-normal liver functions-later than most Despite continued high-dose ste-the course of rejection was unaltered. patient became increasingly debilitated _""i"h high-dose immunosuppression. The clini-I~f course and laboratory findings of rejection "and portal vein thrombosis were similar. We ve since changed our approach to patients with chronic rejection. Once it is determined 'that rejection is irreversible through lack of response to increased immune suppression pathological evidence, retransplantation is considered earlier. The patient's immune suppression is decreased to avoid overimmu-nosuppression. The surgery is often easier r<;"<1r~;y; vital structures already have been skeletonized and the patient is not debilitated from chronic overimmunosuppression. Infection leading to graft failure occurred in 4 (17%) patients and was a contributing in another 3 losses. In patients OT 201 and OT 279A, biliary tract reconstruction may have been the initial inciting event, lead-to biliary sepsis and graft failure. The second liver of OT 259B was grafted to vessels already infected with candida and Pseudo-monas aeruginosa. OT 191 emphasized --Starzl's concept of septic hepatic gangrene.s The patient had a large fungal abscess. The homograft injured from rejection or vascular ..insult is much more susceptible to infection I than one not injured. I ee~ati~ homograft loss was a frequent . I complIcatIon of transplantation. Acute he-~atic infarction, rejection (despite the use of ; ~sA ~nd steroids), vascular accidents, and , ~ mfectlOn were primary causes of graft failure. ..farly retransplantation may be beneficial in 2595 preventing patient death with initial graft loss . Surviving Grafts The current status of 27 surviving patients is listed in Table 3. One patient recently underwent a third transplant (not in the time frame discussed above) and will not be included in the following discussion. Of the 26 remaining survivors, 24 (92%) have bilirubins under 1.5 mg/dl. Of the 2 patients with elevated bilirubins, OT 206 has chronic rejec-tion and may require retransplantation; OT 237 has mild rejection due to drastic lowering of immunosuppression because of an intesti-nal lymphoma. OT 206 is the only patient who has an SGOT of > 1 00 IU. Daily prednisone dose averages 0.4 mg/kg/day, and the mean CsA dose is 15.5 mg/kg/day. Cyclosporine doses in patients transplanted prior to 9/82 average only 10 mg/kg/day. Patients trans-planted subsequently, however, have an aver-age dose of 25.6 mg/kg/day. Generally, this dose is able to be decreased to 8-10 mg/ kg/day within the first postoperative year.9 It appears, therefore. that the vast majority of surviving grafts have excellent function. CONCLUSIONS Hepatic homograft failures occur fre-quently (42%) and remain a major cause of morbidity and mortality in pediatric liver transplant patients. Graft infarction (33%), rejection despite the use of CsA and steroids (29%), vascular accidents (21%), and infec-tion (17%) are major causes of graft failure. Attempts to control rejection may involve using higher doses of CsA than previously accepted, and children may tolerate larger oral doses with little nephrotoxicity. Despite a 30% retransplantation rate, 92% of surviving grafts are associated with bilirubins of < 1.5 mg/dl, indicating excellent function of surviv-ing grafts. ADDENDUM Since submission of this manuscript, OT 206 underwent successful retransplantation for chronic rejection. Her bilirubin and enzymes are within normal limits. 2596 ZITELLI ET AL. REFERENCES I. Starzl TE. Iwatsuki S. Malatack JJ. et al: J Pediatr 100:681.1982 2. Starzl TE. Iwatsuki S. Van Thiel DH. et al: Hepa-tology 2:614.1982 3. Malatack JJ. Zitelli BJ. Gartner JC. et al: Trans-plant Proc 15: 1292. 1983 4. Sawchuk RJ. Cartier LL: Clin Chem 27: 1368. 1981 5. Starzl TE. Putnam CW: In Experience in Hepatic Transplantation. Philadelphia. Saunders. 1969 6. Porter KA: Transplant Rev 2: 129. 1969 7. Fennell RH. Roddy HJ: Pathol Ann 14(2):155. 1979 8. Groth CG. Porter KA. Otte JB. et al: Surgery 63:658. 1968 9. lwatsuki S. Starzl TE. Shaw BW Jr. et al: Long-Term Use of Cyclosporine in Liver Recipients: Reduction of Doses in the First Year to Avoid Nephrotoxicity (Paper presented to the American Society of Transplant Sur-geons. Chicago. June 3. 1983) Regis The t plants and D this re 

HEPATIC HOMOGRAFT SURVIVAL IN PEDIATRIC ORTHOTOPIC LIVER-TRANSPLANTATION WITH CYCLOSPORINE AND STEROIDS

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HEPATIC HOMOGRAFT SURVIVAL IN PEDIATRIC ORTHOTOPIC LIVER-TRANSPLANTATION WITH CYCLOSPORINE AND STEROIDS

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