Iwaki, Y

Starzl, TE

Takaya, S

English

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Liver Transplantation in positive cytotoxic crossmatch cases using FK506, high dose steroids and prostaglandin E1

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LIVER TRANSPLANTATION IN POSITIVE CYTOTOXIC CROSSMATCH CASES USING FK506, HIGH-DOSE STEROIDS, AND PROSTAGLANDIN E

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---------- -----------------------Reprinted from transplantation Volume 54, Number 5, November 1992 Copyright © 1992 by Williams & Wilkins LIVER TRANSPLANTATION IN POSITIVE CYTOTOXIC CROSSMATCH CASES USING FK506, HIGH-DOSE STEROIDS, AND PROSTAGLANDIN Ell Although the liver is resistant. to antibody-mediated rejection (1), a significant adverse effect has been reported of its trans-plantation into recipients with preformed cytotoxic antibodies (2). We report here a strategy that appears to convert the prognosis in such potentially disadvantaged patients to essen-tially the same if not better than that in conventionally treated crossmatch-negative recipients. The crossmatch status was determined with recipient sera treated with dithiothreitol (DTT) (3). Four cohorts of adult liver recipients were studied. In all, intravenous FK506 was started with doses of 0.075 to 0.15 mg/kg/day, and converted to oral dosing after resumption of diet. Treatment was guided by plasma FK5061evels (target approximately 1 ng/ml), toxic-ity (primarily renal), the clinical status of the patient, and the quality of postoperative liver function (4). The 4 study groups (Table 1) differed in the cytotoxic crossmatch state (negative in group 1 only), the use of prostaglandin EI (group 4 only), and the prophylactic use of methylprednisolone (MP). Low-dose MP was with 20 mg/day starting on the day of trans plan-tation (most of group 1 and all of group 2). High-dose MP was with 1 g Lv. during operation, followed by a "burst" with 200 mg the first day and daily decreases of 40 mg until 20 mg/day was reached on the 6th day if the course was uneventful (groups 3 and 4). In group 4, i.v. PGE, (Prostin VR) was started after completion of the operation with 0.2 ILg/kg/hr and gradually increased to 0.6 ILg/kg/hr if tolerated without cardiovascular instability. One of the 14 patients in group 4 had transient hypotension. There were no other side effects of PGEh which was stopped without weaning when the patients resumed diet after 5-7 days. The crossmatch positive cases in groups 2-4 were consecu-tive, with no omissions. The incidences of hepatic malignancy, high UNOS urgency scores (50-78% III or IV), and cytotoxic titers> 1:8 were similar in the cytotoxic groups 2-4. Females were disproportionately represented in all of the crossmatch-1 This work was -supported by Research Grants from the Veterans Administration and by Project Grant DK 29961 from the National Institutes of Health, Bethesda, MD. positive groups compared with crossmatch-negative controls. In the crossmatch-positive .cases, the outcome was remarkably different according to treatment (Table 1). With high-dose steroid therapy (group 3), the unacceptably high early and delayed graft loss seen with low-dose steroid therapy (group 2) was reduced by two-thirds. Graft loss was reduced further if PGE1 was added to the high-dose steroid regimen (group 4). The only death in the 14 patients of group 4 was caused by a biliary leak and subhepatic infection in a patient whose native gall bladder had empyema. The favorable course of the group 4 recipients relative even to group 3 and especially group 2 patients was reflected by an improvement in the perioperative renal function (Fig. 1), and superior postoperative liver function (Fig. 2). The superior renal function in the liver recipients of group 4 was noteworthy. It is possible the PGE1 specifically protects the kidneys from FK506 nephrotoxicity by a mechanism similar to that described by Makowka et a1. (5) for cyc1osporine. However, protection of the liver graft from antibody-mediated rejection and consequent avoidance of prerenal complications may have been a significant or even more important factor. The pathogenesis of hyperacute rejection of kidney grafts, - TABLE 1. T lymphocytotoxic crossmatch state Group 1 (n=216) 2 (n=28) 3 (n=12) 4 (n=14) Crossmatch Negative Positive Positive Positive Methyl prednisolone Variable Low High High PGE1 No No No Yes Hepatic malignancy 7.4% 3.6% 7.1% 8.3% Male/female 130/86 12/16 0/12 3/11 High-titer (>1:8) 14 9 9 Survival (6 months)· Patient 90.5% 71.4%b 92.3% 92.9% Graft 84.8% 60.7%' 83.3% 92.9% Median follow-upd 454 d 446 d 320d 240d a Actual survival. b Group 1 VB. 2, P=0.0006. , Group 2 vs. 3, P=0.125; group 2 VS. 4, P=O.03. d Follow-up of 6 to 25 months. 928 TRANSPLANTATION Vol. 54, No.5 GROUP2 GROUP3 GROUP4 LOW DOSE STEROID HIGH DOSE STEROID HIGH DOSE STEROID AND PGE1 03,--------------, lKP~------------D 0.3 ra PO FK DOSAGE • IV FKS06 DOSAGE >-~ o iii 0.2 t:l ct VI o o II> ::g 0.1 ~ u.. ~ PO FK DOSAGE • IV FK506 DOSAGE >-« o ffi 0.2 < VI o Cl c.o o ~ 0.1 u.. ~ PO FK DOSAGE • IV FKS06 DOSAGE >-< c ill 0.2 Cl <I: UJ o Cl c.o o ~ 0.1 u.. 2 3 4 5 1 2 3 4 5 6 7 o 2 3 5 POSTOPERATIVE DAYS POST OPERA TIVE DAYS POSTOPERATIVE DAYS 2 l+--r-~r-~-~--r--r-~ o Plasma FK 506 (ng/ml) POSTOPERATIVE DAYS 5.77 ± 0.42 (S.E.) POSTOPERA TIVE DAYS 3.35 ± 0.35 POSTOPERATIVE DAYS 3.64 ± 0.26 FIGURE 1. First-week FK506 doses and plasma concentrations and serum creatinine (Cr) in crossmatch-positive liver recipients (groups 2, 3, 4). (Cr)-group 2 vs. 3 P<O.OOOl, 2 VS. 4 P<O.OOOl, 3 vs. 4 = P = and the much slower manifestations of antibody-mediated re-jection seen in liver grafts are not fully understood (6). What-ever the mechanisms, it has been known since the earliest work of Dempster (7) that intense vasoconstriction occurs of the graft microvasculature (8). PGE] treatment added to FK506 and high doses of steroids could have ameliorated this conse-quence, aside from its inherent immunosuppressive (9) and cytoprotective (10) qualities. Amelioration by PGE] of humoral rejection has not been reported clinically, but there have been clues of its potential value in xenograft transplant models that have heterospecific antibody barriers, including cat-to-dog (1 I), hamster-to-rat (12), and pig-to-dog (13). High-dose prednisone in conjunction with FK506 but without PGE] also was effective. The steroid mitigation of humoral rejection presumably was by different pathways although both glucocorticoids and PGE suppress cytokines (14, 15). Accurate delineation of these drug actions and interactions will be of the greatest interest in providing clues for other therapeutic im-provements. At a practical level, the experience reported herein indicates not only the feasibility but also the surprising ease with which the liver can be transplanted to sensitized recipients. If opti-mum therapy is given, a policy of excluding patients with widely reacting cytotoxic antibodies from candidacy for liver trans-plantation would seem unwarranted. The results in the high-0.007. FK506 dose-2 vs. 3 P<O.OOOl, 2 vs. 4 P<0.0004, 3 VS. 4 = P = 0.2. The average plasma FK506 value in group 2 was significantly higher than in groups 3 and 4 (P = 0.0004). Wilcoxon rank-sum test. dose steroid-PGE1 group 4 were at least as good as in the cases with negative crossmatches. Whether all liver transplantations, including those with crossmatch-negative donors should be given this treatment deserves consideration. PGE] already has been used in this way in cyclosporine-based drug cocktails for crossmatch-negative kidney transplantation (16). There wer ... no obvious artifacts that would undermine these conclusions, such as the use in later cases of a different titer cutoff for a positive-crossmatch reading. About the same per-centage of titers greater than 1:8 were in groups 2-4, but the highest positive titer was not measured systematically at the time of the case accrual. In 6 subsequent patients who were given the optimal recommended treatment and who had titers equal to or greater than 1:256, only 1 had a humoral rejection. This was a female patient with a titer of 1:1024 who required retransplantation 2 days after primary graft nonfunction, using a crossmatch-positive donor liver (titer 1:2) on the second occasion. She is well 4 months later. The influence of titers, different sensitization schedules, and the nature of the antibody upon humoral rejection of the liver in rats has been described elsewhere.4 These experimental studies, combined with our clinical experience herein reported, 4 Furuya T, Murase N, Nakamura K, et a1. Preformed lymphocyto-toxic antibodies: the effects of Ig class, titer and specificity on liver versus heart allografts. (Submitted for publication.) November 1992 BRIEF COMMUNICATIONS 929 SERUM TOTAL BILIRUBIN 14K-------------------------------~ -"t-O 12 E Z m 10 ;:) a:: :::i 8 m ..J « I-o I-:E ;:) a:: w en -;:) -en ..J W > W ..J I-0 (!l :E ;::, a:: w en 6 4 2 1800 1600 1400 1200 1000 800 600 400 200 0 ----I!I--- NEGATIVE - LOW DOSE STEROID --- HIGH STEROID - HIGH+PGE1 ·1 Q 1 2 J. 567 & 9 10111213"1516171819202122232'2526272& -1 0 TIME(DAYS) SERUM GOT NEGATIVE LOW DOSE STEROID HIGH STEROID HIGH+PGE1 2 3 4 5 6 7 8 9 10 11 12 1314 TIME(OAYS) FIGURE 2. Serum total bilirubin (1st month) and serum GOT levels (2 weeks) in crossmatch-positive liver recipients. Bilirubin in first week-group 2 vs. 3 P = 0.007, 2 vs. 4 P<O.Ol, 3 vs. 4 P=0.36. SGOT in first week-group 2 vs. 3 P=O.36, 2 vs. 4 P<0.02, 3 vs. 4 P=0.38. Wilcoxon rank-sum test. have led to our present policy of not delaying urgently needed liver transplantation in order to search for a more appropriately crossmatched donor. SHUNICHI TAKAYA YUlCHI Iw AKlc THOMAS E. STARZL' The Departments of Surgery and Pathology University of Pittsburgh School of Medicine The Veterans Administration Medical Center Pittsburgh, Pennsylvania 2 Department of Pathology, University of Pittsburgh School of Med-icine. 3 Address correspondence to: Thomas E. Starzi, M.D., Ph.D., De-partment of Surgery, 3601 Fifth Ave., Falk Clinic 5C, Pittsburgh, PA 15213. REFERENCES 1. Starzl TE, Ishikawa M, Putnam CW, et a!. Progress in and deter-rents to orthotopic liver transplantation, with special reference to survival, resistance to hyperacute rejection, and biliary duct reconstruction. Transplant Proc 1974; 6: 129. 2. Takaya S, Duquesnoy R, Iwaki Y, et al. Positive crossmatch in primary human liver allografts under cyclosporine or FK 506 therapy. Transplant Proc 1991; 23: 396. 3. Iwaki Y, Lau M, Terasaki PI. Successful transplants across T warm positive crossmatches due to IgM antibodies. Clin Trans-plant 1988; 2: 81. 4. Starzl TE, Abu-Elmagd K, Tzakis A, Fung JJ, Porter KA, Todo S. Selected topics on FK 506: with special references to rescue of extrahepatic whole organ grafts, transplantation of "forbidden organs," side effects, mechanisms, and practical pharmacoki-netics. Transplant Proc 1991; 23: 914. 5. Makowka L, Lopatin W, Gilas T, Falk J, Phillips MJ, Falk R. Prevention of cyclosporine (CyA) nephrotoxicity by synthetic prostaglandins. Clin Nephrol1986; 25 (suppl1): S89. 6. Starzl TE, Demetris AJ, Todo S, et al. Evidence for hyperacute rejection of human liver grafts: the case of the canary kidneys. Clin Transplant 1989; 3: 37. 7. Dempster W J. The nature of experimental second-set kidney trans-plant rejection. Br J Exp PathoI1971; 52: 172. 8. Terada Y, Ueno A. Hyperacute renal allograft rejection in the rabbit: vasoconstriction demonstrated by microangiography. Transplantation 1983; 35: 205. 9. Strom TB, Carpenter CB. Prostaglandin as an effective antirejec-tion therapy in rat renal allograft recipients. Transplantation 1983; 35: 279. 10. Greig PD, Woolf GM, Sinclair SB, et al. Treatment of primary liver graft nonfunction with prostaglandin E,. Transplantation 1989; 48: 447. 11. Mundy AR. Prolongation of cat to dog renal xenograft survival with prostacyclin. Transplantation 1980; 30: 226. 12. Shaw JRL. Role of prostaglandins in transplantation. In: Cohen MM, ed. Biological protection with prostaglandins. Vol. 1. Boca Raton, FL: CRC Press, 1985: 111. 13. Makowka L, Miller C, Chapchap P, et a!. Prolongation of pig-to-dog renal xenograft survival by modification of the inflammatory mediator response. Ann Surg 1987; 206: 482. 14. Rappaport RS, Dodge GR. Prostaglandin E inhibits the production of human interleukin 2. J Exp Med 1982; 155: 943. 15. Lew W, Oppenheim JJ, Matsushima K. Analysis of the suppression ofIL-la and IL-1b production in human peripheral blood mono-nuclear adherent cells by a glucocorricoid hormone. J Immunol 1988; 140: 1895. 16. Moran M, Mozes MF, Maddux MS, et a!. Prevention of acute graft rejection by the prostaglandin E, analogue misoprostol in renal-transplant recipients treated with cyclosporine and prednisone. N Engl J Med 1990; 322: 1183. Received 27 N(}vember 1991. Accepted 6 February 1992. 

Liver transplantation in positive cytotoxic crossmatch cases using FK506, high-dose steroids, and prostaglandin E

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Liver transplantation in positive cytotoxic crossmatch cases using FK506, high-dose steroids, and prostaglandin E

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