Bahnson, HB

Griffith, B

Hardesty, R

Iwatsuki, S

Klintmalm, GBG

Porter, KA

Shaw, BW

Starzl, TE

Van Thiel, DH

English

Shaw Jr, BW

Name not available

Cyclosporin A and steroids for liver and heart transplantation

D-Scholarship@Pitt

ntation. >llow-up ecreased >pressive f heart-t1ccessful .rine and ltral role CyA im-eved this ed States CHAPTER 38 Cyclosporin A and steroids for liver and heart transplantation THOMAS E. STARZL, SHUNZABURO IWATSUKI, HENRY B. BAHNSON, DAVID H. VAN THIEL, ROBERT HARDESTY, BARTLEY GRIFFITH, BYERS W. SHAW, Jr., G. B. G, KLiNTMALM and KENDRICK A. PORTER Departments of Surgery and Medicine, University of Pittsburgh Health Sciences Center, The Veterans Administration Medical Center, Pittsburgh, PA 15261, U.S.A., and the Department of Pathology, Saint Mary's Hospital and Medical School, London, U.K. 1. Introduction Combination therapy with Cyclosporin A (CyA) and steroids has improved the course of patients after cadaveric renal transplantation. Application of this therapeutic advance to the transplantation of cadaveric livers and hearts was a natural extension to be described in this communication. 2. Liver transplantation 29 patients were accepted for the clinical trial for the indications listed in Table 1. 8 of the recipients were in the pediatric age group (2-16 years) and the other 2 I were 20-56 years old. The liver grafts were preserved with Collins solution for 1 ~-T ABLE I: Diagnoses in 29 liver recipients accepted for clinical trial OIronic active hepatitis "nmary hepatic malignancy (3 hepatoma, one intrahepatic duct cell carcinoma) .&WIY atresia Ivdd -C'hiari Syndrome Secondary biliary cirrhosis P'runOiIY biliary cirrhosis pckro~in~ cholangitis lone with duct cell carcinoma) Illel" Syndrome Alph;a·I·antitrypsin deficiency and cirrhosis hepatic cirrhosis 8 4 4 3 3 2 2 Starz1. T.E .• Iwatsuki S B h r.rlfflth B Sh B ~ ., anson, H.B., Van Thiel, D.H., Hardesty, R., , . , aw, '''. Jr. Klinttnalm G B G d P K A and steroids for Ii d' , ". an orter, .A.: Cyclosporin fWhtte D J G d) ~~r an heart transplantation. In: Cyclosporin A , " _. :_e .:__ sevier Biomedical Press, Amsterdam, pp. 431-436, 1982. " I ! i· I I , ! 432 104- h and transplanted by the same techniques as have been used in the ~a_pcaffK 1969; Starzl et al., 1979). Donor recipient matching for HLA antigens was random. Because of urgent ..... two donors were accepted in spite of ABO incompatibility (A to 0 and A to I), II three more cases, a positive cross match was present with complete kiJIing of ~ lymphocytes by pre-existing cytotoxic antibodies in the recipient serum. It is k~ (Starzl et al., 1979) that the liver is resistant to hyperacute rejection from prefontll4 antibody states. Cy A usually was started a few hours preoperatively at 17.5 mg/kg and .:ontinliM daily, usually with half the dose every 12 h. The quantities were reduced subsequently if toxic manifestations developed, of which suspected nephrotoxicity (Fig. I) wu the most important. 8 z as '" It-=-~ iDi :I E ",-It ., <II 0 Z "'-a.# ~ E o:r ., <II ., L f~l !'i ~ E 100 .,- 50 f a .. i !lao ~ .. UE - 1000 b s ,j. s ,j. 10 s ,j. 47 YEAR OLD ~ 44k~ S. I GRAM HYDROCORTISONE IS 20 TIME IN DAYS Fig. 1. Cy A and steroid therapy in a woman with a hepatoma whose cirrhosis was too severe to permit subtotal hepatic resection. Note the 5 day initial burst of prednisone therapy, and the adjustment ofCyA dose as the BUN rose. In the Colorado part of the series, steroids were not given at first in half of the cases. When it became evident from clinical observations and biopsy evidence that rejection was common, steroids were begun on the day of operation. Adult patients who did not have profound metabolic abnormalities and who left the operating room in good condition were given the 5 day burst of prednisone described elsewhere in this symposium for renal recipients, starting at 200 mg and stopping with a maintenance of 20 mg per day (Fig. I). Initial and maintenance therapy were scaled down in infants and children. If the patient was in poor condition, high dose initial therapy with ster-oids was omitted (Fig. 2). 11Ie \4 patients wer( pitttu died on the ( IIOt treated with irr operatively of hepati All of the other \he twO intra-operat \he one year surviv; (Stanl et aI., 1981a .entional immunosu paft function desp CyA series. Two patients die giocarcinoma from drome. Nine (64.31 but one have norrr Cy A and prednison ~ ~ o-~--II # 01 \ 1\_ ~u£ v----'" '" '" E ~ PM~ 0-~!K 20 ~b w- 10 0: Q._ 0 .. E ... ~ 500 u! __ o Fig. 2. Omission' risk of pulmonar \ to the University dose of Cy A has l ---r-----'----433 the past (Starz!, of urgent need, and A to B). In killing of donor urn. It is known from preformed g and continued ;ed subsequently (Fig. 1) was the was too pC~" .. thtDrar~K and dill 51 in half or till y cvidcnlX ..... . Adult pa~ uperallllJ roaII :fsewh~"I" .. malflt~" down Ill."" . fcrar~ wiG" \ 2.1. Colorado series \ l ;It 1 The 14 patients were operated upon between March and September 1980. Two reci-pients died on the operating table (Table 2) from technical complications and were not treated with immunosuppression. One of the remaining 12 died 19 days post-operatively of hepatic artery thrombosis. All of the other 11 patients lived through the first post-operative year. Including the two intra-operative deaths, the one year survival was 78.6%, and excluding them, the one year survival was 92%. Many complications which were treated successfully (Starzl et ai., 1 98la,b ) were the kind which had been almost always lethal under con-ventional immunosuppression (Starzl et ai., 1969, 1979). The ability to maintain good graft function despite low-dose steroid therapy was the distinguishing feature of the CyA series. Two patients died after a year (12 and 16 months). One had recurrence of a cholan-giocarcinoma from her native liver, and the other from recurrent Budd-Chiari syn-drome. Nine (64.3%) of the original 14 patients are still alive after 1-1 t years, and all but one have iI-ormal or near normal liver function. Of those 12 actually treated with CyA and prednisone, the present survival is 75%. 10 YEAR OLD ~ 23 Ko 20 a-r' Iii 10 0 i~ I r I ( 0 r--1- 30 l~ 20 r 10 0 ~i !OO ,,! 0 ~ to f~ 20 TIME IN DAYS ,.. 2. Omission of steroid burst therapy in a H)-year-old boy who was thOUght to be at increased .. of pulmonary infection because of a recent gastrointestinal haemorrhage. He was transferred .. lilt University of Pittsburgh from the Intensive Care Unit of a hospital in a distant city. The full ... of Cy A has been well tolerated, 434 TABLE 2: Causes of death in Denver series of liver transplantations in CyA era (\4 p~f~"D" Operative Hepatic artery thrombosis (19 days) Recurrent malignancy (12 months) Recurrent Budd-Chiari Syndrome (16 months) • Not treated with immunosuppression. TABLE 3: Causes of death in Pittsburgh Series (15 patients) Poorly preserved livers (with technical errors (without technical errors Systemic aspergillosis 2.2. Pittsburgh series 2' 4 2) 2) 1 15 patients were accepted for the trial. The first 4 (all adults) died after 4 to 16 days (Table 3). A feature common to these consecutive disasters was poor initial liver fun~· tion including failure of clotting; technical errors in biliary tract reconstruction were also committed in two. Multiple organ failure and uncontrollable infections ensued. At autopsy, the livers had widespread necrosis but little or no evidence of rejection. A deviation had been made from the previously standardized harvesting procedure leading to de.emphasis or omission of cooling by the portal venous route, and reliance on in situ hepatic arterial cooling. After correction of this error, uniformly adequate livers were obtained and 10 of the next II recipients have survived for 1-4~ months. All but one have been discharged from the hospital, including a child whose first liver was replaced with another graft after two weeks because of a huge Candida abscess which destroyed much of the right lobe. The only death in the last 11 cases was from disseminated aspergillosis at 8 days in a patient who was in Stage 4 hepatic coma prior to operation. Liver function is normal or near normal in the 10 survivors. Nephrotoxicity of Cy A in liver recipients has been studied by Klintmalm et al. (1981). Renal dysfunction was usually correctable by downward adjustments of CyA dosage. However, one patient required hemodialysis. No examples of CyA hepatotoxi· city have been recognized. 2.3. Actuarial survival in combined series Even including the two operative deaths in the Colorado series and the four flawed cases in the Pittsburgh series, the one year life expectancy has been raised to better than 70% in the CyA era, twice as high as in our previous total experience (Fig. 3). Caine et a1. (1981) have reported a similar recent improvement corresponding to their use of CyA. Calne et al. (1979) were the first to use eyA in clinical liver transplanta· tion. LIVER TRANSPL ___ CYCLe ...---. HISle;: 0<005 MONTHS POST·TR; fig. 3. One year actuari, uyra"p~ratively and 4 \\ ye31 survival of histoIlCal 3. Cardiac transp/u The University of Pit formed 7 heart tran late july 1981. Beca function could be ae depicted in Fig. 1 in These cases, inch ratelv. 6 of the 7 re Efro~ infection and serum contained an was not known abo was badly damaged. 4. Discussion and The grafting of org, transplantation, in cial kidney did not ably as has been n extra renal organs' principles of immu edly be applicable t --- ,- ----------T---er"tl4l'illlenlsl \ 2· 1 4 2) 2) I lfter 4 to 16 days . initial liver fune-onstruction were :tions ensued. At rejection. 'esling procedure 'ute, and relian" : ained and 10 of ~ been discharged ith another graft ed much of the J aspergillusi) at 1. Liver function ~lintmalm et aI. lstments of (yA :yA hepatoloU-the four flav.·td raised to ben~ 'rience (F is, 3). londing to thnr ver transplan" I 435 LIVER TRANSPLANT --. CVClOSPQRIN A ~KK" 291 .-..-.. HISTORICAL CONTROLS In' 170) 40 20 p<OOl 6 '2 MONTHS POST· TRANSPLANT Fig. 3. One year actuarial life survival curve of the last 29 liver recipients, including two who died intraoperatively and 4 who received livers that were damaged by poor preservation. The actual one year survival of historical con trois also is shown, 3. Cardiac transplantation The University of Pittsburgh cardiac transplantation team (H. B. B., R. H., B. G.) per-formed 7 heart transplantations under Cy A and steroid therapy from early April to late July 1981, Because no interval, however brief, of rejection and ineffective cardiac function could be accepted, the steroid withdrawal was done more gradually than that depicted in Fig. 1 in a liver recipient. These cases, including their special management problems, will be reported sepa-rately. 6 of the 7 recipients (all adults) are alive after 1~-R months. The only death (from infection and heart failure) was at 10 weeks of a 48-year-old woman whose serum contained anti-donor T warm cytotoxic antibodies. The positive crossmatch was not known about in advance. Although the heart escaped hyperacute rejection, it was badly damaged. 4. Discussion and Conclusions Tht grafting of organs such as liver and heart has not had the wide application of renal transplantation, in part because artificial life support systems analogous to the artifi-calltidney did not and do not exist. With the ability to control rejection more predict-Ibl)' as has been made possible with Cy A and steroids, interest in transplantation of otra renal organs will surge. Although each organ will have special requirements, the pnnciples of immunosuppression evolved with the simple kidney model will undoubt-.. tdIy be applicable to all. ; i 436 Acknowledgements This work was supported by grants from the Veterans Administration, grants C4M-17260 and AM-07772) from the National Institutes of Health, grants (RR·OOQSI .. RR·00069) from the General Clinical Research Centers Program of the Division 01 Research Resources, National Institutes of Health, and a grant from the ~edaal Research Council of Great Britain. References CaIne, R. Y., Rolles, K., Thiru, S., McMaster, P., Craddock, G. N., Aziz, S., White, D. 1. G .. F\'lIt\. D. B., Dunn, D. c., Henderson. R. G. and Lewis, P. (1979) Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 liven. Lancet 2, 1033-1036. CaIne, R. Y., Williams, R., Lindop, M., Farman, J. V., Tolley, M. E., RoUes, K., MacDougall 8.. Neuberger, 1., Wyke, R. J., Raftery, A. T., Duffy, T. 1., Wight, D. G. D. and White, D. J. G. (1981) Improved survival after orthotopic liver grafting. Brit. Med. J. 283,115-118. Klintmalm, G. B. G., Iwatsuki, S. and Starzl, T. E. (1981) Nephrotoxicity of Cyclospofln A III liver and kidney transplantation. Lancet 1, 470-471. Starzl, T. E. (1969) Experience in Hepatic Transplantation. W. B. Saunders Co., Philadelphia. Starzl, T. E., Koep, L. 1., Halgrimson, C. G., Hood, 1., Schroter, G. P. 1., Porter, K. A. and Wei! lIl, R. (1979) Fifteen years of clinical liver transplantation. Gastroenterology 77, 375-388. StaTZI, T. E., Iwatsuki, S., Klintmalm, G., Schroter, G. P. 1., Weil, R. III, Koep, L. 1. and Porter. K. A. (l98la) Liver transplantation, 1980, with particular reference to Cyclosporin A. Trant· plant. Proc. 13, 281- 285. Starzl, T. E., Klintmalm, G. B. G., Porter, K. A., Iwatsuki, S. and Schroter, G. P. 1. (l981b) Liver transplantation with use of Cyclosporin A and prednisone. New Eng. 1. Med. 305, 266- 269. Clinica eye JOHN J. RYNASi INpartment of Surge! 1. [ntroduction 171 pancreas tranSl 1966 and 1 Septen were treated with prednisone, with o! eyte preparations. -low, in part due te pressive regimen v.. national Human Pa had functioning gr planted after 191' than one year aftr tion. A total of 46 r the University of 1966 and 1973 I first 11 in uremic the last three in f ventional immun died with functio! rejected. In 1978 panel the segmental tel performed betw< Sutherland, 198: , . ~~:~~:;K ~>-l ·'1 <,\><' I~ .i' -t;;-:."\. ~~_~KD" ,,: ' .> qyK~" tD;-~ ,. ~K~KK:KKIII ~ IN-"'" ,.,.,... ~ Of: l • ~ ~K '01 • 

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Cyclosporin A and steroids for liver and heart transplantation

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