Demetris, J

Eiras, G

Furukawa, H

Imventarza, O

Oks, A

Starzl, TE

Todo, S

Ueda, Y

Wu, YM

Zhu, Y

English

D-Scholarship@Pitt

Renal Transplantation in Baboons Under FK 506 O. Imventarza, S. Todo, G. Eiras, Y. Ueda, H. Furukawa, Y.M. Wu, Y. Zhu, A. Oks, J. Demetris, and T.E. Starzl B EFORE embarking on a clinical trial of FK 506. the effectiveness and safety of this agent were examined with exhaustive animal studies in rats. dogs. and subhu-man primates. Reponed here are the results of baboon experiments. with renal transplantation and correlation with parallel in vitro mixed lymphocyte reaction (MLR) determinations. Part of this work was previously reponed elsewhere. 1.2 MATERIALS AND METHODS Unrelated female baboons. weighing 8 to 14 kg. were used. Renal iransplantation was perfonned intraabdominally. Ureteroneocys-tostomy was made following removal of the native kidneys of the recipients. Lymphocyte sensitivity to FK 506 in rats. dogs. and baboons was determined using the one-way MLR. which IS standard in our laboratories. ~ RESULTS Dose-Dependent Study Stanmg on day 4. the baboons were given oral FK 506 in doses of 0 mglkgd In = 41. 2 mg/kgJd (n = 2).6 mgkgd In = 41. 12 mgkgtd (n = 51. and 18 mglkgld (n = 51. In addition. FK 506 was given to animals intramuscularly for the first 3 days. The oral medication was continued for 90 days. Using 90 da\S as a ceiling for calculation. th~ mean animal sunl\ al \10 a~ 9.2 = 4.0 f SOl days at 0 mg.kg. d. 1 n = 2.0 da~s at 2 mg k.g. d. 29.5 = 21.2 da~Ds at 6 mglkg d. 70.8 = :-.6 days at I: mgkgd. and 74.6 = 28.9 da\\ at 18 mg kg.d f Fig I). civ~ animab receiving 12 or 18 mg. "g FK 506 li\fd for mort! than 90 days. Graft Function anc Pathology of Allograft Rt!nal faIlure dt!\ t!lllred raphjl~ 10 bilboon~ r..:e":l\ Ing nl' FK S(lf> trcatmt!n!. while tho,e gl\..:n FK S(lf> ,hoI' cd 0'" 0-3 Oly •. 9C ·m I ' P 0,\ 1102 05 . ,. 1.0 _ft. 20 '2 20 ,. "I , 0 ,. ]. •• SO I. '0 e", , Fig 1. Mean su'\wal 01 baboons treated With different doses of FK 506 after rena transplantation dose-dependent maintenance of graft function. Histo-pathologic analyses of renal allografts in baboons who died within 90 days showed moderate to severe rejection. with the exception of two animals who died of pyelonephritis and unknown causes .. Hepatic Fundion and Blood Glucose Hepatic function and blood glucose levels were normal and not significantly different in untreated and treated animals (Table I). FK Blood levels Blood levels were determined by an enzyme immunoassay using monoclonal antibody to FK 506. J Although the doses given to animals varied between groups. there was no statistical difference in the blood levels (Table I). Histopathology of Extrarenal Organs Specimens were collected at autopsy from 15 animals that died within 90 days. In five other baboons. a bior~~ of the graft was performed at 90 days: these biopsies sh,w'ed no imponant abnormalitIes in the Ii\ t!r and pancreas that were suggestive of drug side effect. Tht!re was no anent IS in any organs from any of the animal~ except for fibrinolJ change of a single vessel in the appendi\ and the stomach. Long·term Observations After Discontinuing FK Treatment Of five animals who li\ ed for more than 90 ":.1\ s after 'tl)PPlng oral FK Ircatmen!. four IubDcquentl~ ":c\elopcd allograft rCJeCtlllO. :\ KD·da~ cour,c of inlrgmrDcu:Kl~ FK ~Eltt Ircatment. 2 mg."!:! d. r..:\..:r,ed rC.leClillO 10 1\\,' IJf thKK:D~ fllur ammal". but \.la, nIH etf,,:cl!\C \\lIh the 11Ih,," 1\\0 .. -\11 four anima'" dl~d e\ ~ntuall~ of Llrgan reKle~tllln The tifth aOlma!. II hleh ne\ cr h<.ld a r":Jcctllln. 1\ a, "I:: ~g at ~Kg~ dav,. in a health\ 't.lte ,JOd <It J tlm~ \thcn r~nK!K iunetll)n II<.1S normal. Therc \loa, nll hl'tlllelgl': Jbnllrm.! .. I~ in t~lD "fdnKK:~ Ilr other organ, . From the Departments Of Surgery and Pathology. ;"'1IVersll'y of Plnsburgh School of MediCine. ana Ihe Veterans AC-lOlstrat,on. Pinsburgh. PA. Supported by research grants from the Veterans A:~lllstralion and PrOject Grant No DK 29961 'rom the NallOna ~stltutes of Health. Bethesda. MO Address reprint reauests 10 T E Slarzl. MO. PhD. C ~=Iart"Ie~t of Surgery. 5C Falk CliniC. 3601 Fifth Avenue. PltlSbur;- PA 15213 c 1990 by Appleton & Lange 0041·134590 $3 00 -0 64 TransplantatIon Proceedings. Vol 22. No 1. SUPOI 1 (Februaryl .• ~;KlK pp 64·65 RENAL TRANSPLANTATION IN BABOONS UNDER FK 506 65 Table 1. Postoperative SGOT. SGPT. Total Bilirubin. Blood Glucose. and FK 506 levels In Baboons In Groups 1 to 5 Dose 01 Oral FK 506 SGOT Group Imgkgd) No. (UI) 0 4 49.5:: 49.5 2 2 2 38.7:: 19.7 3 6 4 45.0:: 20.3 4 12 5 51.0:: 28.8 5 18 5 49.4:: 30.9 Sensitivity of Baboon Lymphocytes to FK 506 In the early stage of the baboon experiments, immunosup-pression by FK 506 was unsuccessful. even when much higher doses than those given in earlier canine ex-periments" were used. From this finding arose the question as to whether there was a difference in the sensitivity of lymphocytes to this agent between species. The results with MLRs under different concentrations in the medium show that cells from the baboon need a dose of FK 506 10 times higher than that needed by dogs or humans to suppress the MLR reaction (Table 2). This information is being reponed separately. 2 DISCUSSION Our greatest concern was the potential toxicity of FK 506. which has previously been reponed to cause diabetes. Table 2. Species Differences In the Sensitivity of lymphocytes to FK 506 FK 506 ConcenlratJOn OptIOnal to Achreve a SO", Oral Inhlbrtoon 01 MLR Dose Ing-ml) (mg kg d) Aat 0.33 :: 0.2 1·2 Dog 0.59 :: 0.58 1·' 5 Baboon 3.85:: 2.0 '2·18 Human 0.29:: 0.2 0.15·03 Serum Total BlOod Plasma SGPT BilIrubin Glucose FK S06 (U I) (mgdl) (mgdl) 1"9 mI) 12.0:: 13.7 0.7:: 0.4 103 :: 4 37.4 :: 40.5 0.5:: 0.5 87:: 78 1.26:: 1.20 25.4 :: '7.6 0.4:: 0.4 104 :: 20 4.27:: 2.87 29.7:: 28.6 0.2:: 0.2 86:: 76 3.26 :: 1.85 36.4:: 64.6 0.4:: 0.8 102 :: 43 5.24:: 5.00 lassitude, arteritis, and other serious problems in baboons. ~ However, none of these major toxicities was seen in our baboon experiments, even when the FK 506 dL'se given daily over a 3-month period was 10 times higher than the dose causing lethal emaciation in dogs. 4 The unexpectedly high dose required for prevention of allograft rejection in baboons correlated with the relative resistance of baboon lymphocytes to this drug. as shown with MLR testing. In addition, the in vitro experiments showed that human lymphocyte sensitivity was closer to that of dogs, a finding that was confirmed in our clinical experience.'" Therefore, FK 506 was a safe and effective immun~Dsuppressive agent for renal transplantation in ba-boons. These experiments were performed in preparation for a clinical trial. REFERENCES I. Tlxj.> S. Demelm:\. L'eda Y. et al: Surgery 1MS:~K 1989 :. Eir.:., G. Imventarza O. yfura~e S. et al: Transplantation (in press) ~K Tamura K. Koi:-a\ashi \1. Hashimoto K. et al: Transplant Pro.:: 19:~K 19117 E~uppfS1 .I. T,xj., S. \Iura,.: S. L'eda Y. et al: Transplant Proc :l:~1RK 19~~ hU,rl I) < Th::"'J S. Cllllier D SI J. C Jlne R Tr;Jn'rl.lnl Proc fDg:I!~K 14~T I ,urrl " ,.., S!.,-zl TE. Tlld,'" cun~gK el al ian,el: II)()(). I'!"'! 

Renal transplantation in baboons under FK 506

Demetris, AG

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Renal transplantation in baboons under FK 506

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