Duquesnoy, R

Fung, JJ

Griffin, M

Shaw, B

Starzl, TE

English

PubMed

Fung, J

Starzl, T

D-Scholarship@Pitt

Successful Sequential Liver-Kidney Transplantation in a Patient With Preformed Lymphocytotoxic Antibodies J. Fung. M. Griffin. R. Duquesnoy. B. Shaw. and T. Starzl SENSITI ZA TION of potential transplant recipients by formation of Iymphocyto-toxic antibodies can be a result of prior blood transfusions, pregnancy. or failed allograft transplantation. While the presence of pre-formed anti-HlA-A and -B Iymphocytotoxic antibodies does not appear to influence the survival of liver allografts; this has been a contraindication in renal transplantation be-cause of the high incidence of hyperacute rejection.' We report a case of successful transplanta-tion of a renal allograft. in the face of a positive warm T cell crossmatch sequentially following a prior hepatic allograft transplan-tation from the same donor. MATERIALS AND METHODS Patient A G,P,Ao. 43·year-old white female, with the diagnosis of primary biliary cirrhosis and renal failure due to intentitial nephriti$, praented (or combined liver-kidney transplantation. Preoperatively. serum BUN was 42 mg/ dL. serum creatinine (Cr) of 3.6 mg/dL. with a Cr clearance of 22 (X/min. Liver and renal allografts were harvested from a single donor and transplanted in a standard manner'-" with baseline cyclosporine and Ite-roids, placing tbe liver and then the kidney allografts. Allograft function was monitored by biochemical and radiologic studies. Histocompatibility Studies These studies consisted of determination of the percent penel reactive antibodies (PRA). and donor fymphoc:yt~ tollie croumatches usi", serum aamples obtained as follows: (I) pretransplant (PRE-OT /KT). (2) postliver, prekidney transplant (POST -OT /PRE-KT). and (3) posttransplantation (POST -OT /Kn. Donor Iymphocy-totollic croumatches (DLC) were clone using I standard modified Amo& Technique. Immu1lOQbsorpt;ons Immunoabsorptions of test aamplc:s were done on pooled buman platelets at a I: I dilution for 60 minutes x 2. while absorptions 01 mouse antibodies were done on solid pbuc anlimouse antibody beads at a 2: J dilution. RESULTS Posllransplant Course Following completion of both the liver and kidney transplant. immediate function of both grafts was noted. Posttransplant evaluations of renal function by both renal ultrasound and radionuclide flow scans indicated normal function. and that the allograft was largely responsible for urinary excretory function. Posttransplant liver function tests demon-strated a similar fall in both total bilirubin (TBll) and transaminase levels. However. nine days following transplantation. elevation of TBIl and biopsy-proven rejection occurred in the hepatic allograft. with normal kidney function. An )) -day course of OKT3s was used to reverse the hepatic rejection. Follow-up of 15 months revealed normal renal and he-patic function without further episodes of rejection. HLA Evaluation PRE-OT /KT sample was strongly positive (1 :64 dilution) in OLC assays. Eight hours following completion of the liver transplant. the POST-OT /PRE-KT sample was negative by standard crossmatch tcchniques. POST-OT /KT samples were analyzed for reappearance of Ole. All samples remained negative for OlC until day 9 posttransplant. when OKT3 was started. This monoclonal . murine antibody has been shown to bind complement. As shown in Fig I. PRA in nonabsorbed POST -OT /KT. also increased From IIw ikpiUt_lIls 0/ Su'pry IlItIl I'lJtltolOD'. U,,;wrsity oj /'illsbu"h. Addnss nprilll ~flrsu 10 J. FUll,. ikptUt_"t 0/ Swrpry. Ulliwrsily 0/ /'iltSbw'lh.1/8 FIJIIc CliNe. JSOI Fifth Aw, /'illsbu"h. PA 1511J, C 1987 by GMI. & StrlJIIOII, IIIC. 0041-1 J45/87/1901....()155SOJ.OO!O 767 718 100 S'a', OK T 3 510£1 OK T 3 c cz: . f/-~Ky a. 50 W·· .. I . .... \ ~ . ' ...... ... l+l----~---r----I_--_r----r_ -, 0 5 10 , 5 20 2S TIME AFTER LIVER-KIDNEY TRANSPLANi Fig 1. Percent panel r .. etM antibody ("PRAI it a.prMaed aa a function of tima following aaquantiel liver-kidnay tranaplantation. OKT3. givan (int.avanoua-Iy) IV. wal atarted on day •• and finiahad on day 20. Open triangular pointl raitact "PRA prior to ablorption on a !IOlid pM" antimou" IgG immunoabaorbant. Cloaecl circla. ara the corra.ponding "PRA valua. fol-lowing Immunoabaorption. during the period of OKT3 therapy. This artifactual rise in DLC and PRA during the period of OKT3 therapy was shown by absorption of POST·OT /KT samples on anti-mouse antibody solid phase beads. Following absorptions, a fall in the % PRA to near levels found prior to and following OKT3 therapy was noted (Fig I). Similarly this absorption removed DLC in the same period. Immunogenetic analysis of the antibody population present in PRE-OT /KT and absent in POST-OT /KT samples revealed a HLA-B·35-associated specificity. This was FUNG El At. confirmed by elimination of DLC and PRA in PRE·OT /KT samples. DISCUSSION The mechanism by which the liver is pro-tected from preformed antibody states in transplantation is not known. I h has not been clarified whether this reflects the unique architecture of the liver, the distribution of HLA antigens within the liver, or the possibil-ity that the liver is able to "neutralize" spe-cific antibodies by release of soluble HLA antigens. Starzl and coworkers first demon-strated that sequential liver-kidney trans-plants in presensitized dogs could protect the renal limb from acute rejection.6 This has been subsequently confirmed in the murine model.' The current study demonstrates the ability of sequential liver-kidney transplantation in the prevention of hyperacute renal rejection in a patient with demonstrated preformed anti-HLA Iymphocytotoxic antibodies. The dramatic and sustained fall of DLC was tem-porally related to placement of the liver allo-graft. This was most likely due to absorption or neutralization of antibodies by the donor liver, and not by dilutional effects. , The applicability of the concept of multior-gan transplantation in transplanting potential presensitized renal transplant candidates is, of Cf>urse, limited, but the mechanisms of protec-tipn using this model, if defined, may provide clues for less drastic therapeutic approaches. REFERENCES I. IwalJulti S,lwalti y, Kano T. et al: Trall$plant Proc 13:286. 198 I 2. Kiamcyer-Nie\sen F. Olsen S. Peterson V, C\ al: Lancet 2:662. 1966 3. Surzl T. IwalJuki S. Esquivel C. et al: Semin liver Dis 5:349. 1985 ... Surzl T. Marchioro T. Dicltinaon T. et al: Arch Surl 89:87. 1%4 .5. Fung J. Ocmetris A. Porter K. et al: Nephron (tn press) 6. Simpson K. Bunch 0, Amcmiya H. et al: SU'lery 68:77.1970 7. Kamacia N. Davies H. ROIef B: Nature 292:840 . 1981 It 

Successful sequential liver-kidney transplantation in a patient with preformed lymphocytoxic antibodies

Successful Sequential Liver-Kidney Transplantation in a Patient With Preformed Lymphocytotoxic Antibodies J. Fung, M. Griffin, R. Duquesnoy, B. Shaw, and T. Starzl SENSITIZATION of potential transplant recipients by formation of Iymphocyto-toxic antibodies can be a result of prior blood transfusions, pregnancy, or failed allograft transplantation. While the presence of pre-formed anti-HLA-A and -B Iymphocytotoxic antibodies does not appear to influence the survival of liver allografts, 1 this has been a contraindication in renal transplantation be-cause of the high incidence of hyperacute rejection. 2 We report a case of successful transplanta-tion of a renal allograft, in the face of a positive warm T cell crossmatch sequentially following a prior hepatic allograft transplan-tation from the same donor. MATERIALS AND METHODS Patient A GJPJAo, 43-year-old white female, with the diagnosis of primary biliary cirrhosis and renal failure due to interstitial nephritis, presented for combined liver-kidney transplantation. Preoperatively. serum BUN was 42 mg/ dL, serum creatinine (Cr) of 3.6 mg/dL, with a Cr clearance of 22 cc/min. Liver and renal allografts were harvested from a single donor and transplanted in a standard mannerJ.4 with baseline cyclosporine and ste-roids, placing the liver and then the kidney allografts. Allograft function was monitored by biochemical and radiologic studies. Histocompatibility Studies These studies consisted of determination of the percent panel reactive antibodies (PRA), and donor Iymphocyto-toxic crossmatches using serum samples obtained as follows: (I) pretransplant (PRE-OT /KT), (2) post liver, prekidney transplant (POST-OT /PRE-KT), and (3) posttransplantation (POST-OT jKT). Donor Iymphocy-totoxic crossmatches (DLC) were done using a standard modified Amos Technique. lmmunoabsorptions Immunoabsorptions of test samples were done on pooled human platelets at a I: I dilution for 60 minutes x 2, while absorptions of mouse antibodies were done on solid phase anti mouse antibody beads at a 2: I dilution. RESULTS Posttransplant Course Following completion of both the liver and kidney transplant, immediate function of both grafts was noted. Posttransplant evaluations of renal function by both renal ultrasound and radionuclide flow scans indicated normal function, and that the allograft was largely responsible for urinary excretory function. Posttransplant liver function tests demon-strated a similar fall in both total bilirubin (TBIL) and transaminase levels. However, nine days following transplantation, elevation ofTBIL and biopsy-proven rejection occurred in the hepatic allograft, with normal kidney function. An II-day course of OKT3 5 was used to reverse the hepatic rejection. Follow-up of 15 months revealed normal renal and he-patic function without further episodes of rejection. H LA Evaluation PRE-OT /KT sample was strongly positive (1 :64 dilution) in DLC assays. Eight hours following completion of the liver transplant, the POST-OT /PRE-KT sample was negative by standard crossmatch techniques. POST-OT /KT samples were analyzed for reappearance of DLC. All samples remained negative for DLC until day 9 posttransplant, when OKT3 was started. This monoclonal ,murine antibody has been shown to bind complement. As shown in Fig 1, PRA in nonabsorbed POST-OT /KT, also increased From the Departments of Surgery and Pathology, University of Pittsburgh, Address reprint requests to J, Fung, Department of Surgery, University of Pittsburgh. 218 Falk Clinic. 3501 Fifth Ave, Pittsburgh, PA 15213, © 1987 by Grune & Stratton, Inc. 0041-1345/87/1901-0255$03,00/0 Transplantation Proceedings, Vol XIX, No 1 (February), 1987: pp 767 - 768 767 I' 768 100 Start OKT3 Stop OKT3 4: a: , ~~~ , / \ , A 0.. 50 UA ~ 'A .'" ~ \ .... ' y~ ....... • ~~ •• --i '.' ~ l~-----r----K----K-----K----K---10 5 10 15 20 25 TIME AFTER LIVER-KIDNEY TRANSPLANT Fig 1. Percent panel reactive antibody (%PRA) is expressed as a function of time following sequential liver-kidney transplantation. OKT3. given (intravenous-ly) IV. was started on day 9. and finished on day 20. Open triangular points reflect %PRA prior to absorption on a sc,lid phase antimouse IgG immunoabsorbent. Closed circles are the corresponding %PRA values fol-lowing immunoabsorption. during the period of OKT3 therapy. This artifactual rise in DLC and PRA during the period of OKT3 therapy was shown by absorption of POST -OT /KT samples on anti-mouse antibody solid phase beads. Following absorptions, a fall in the % PRA to near levels found prior to and following OKT3 therapy was noted (Fig I). Similarly this absorption removed DLC in the same period. Immunogenetic analysis of the antibody population present in PRE-OT jKT and absent in POST-OT /KT samples revealed a HLA-B-35-associated specificity. This was FUNG ET AL confirmed by elimination of DLC and PRA in PRE-OT /KT samples. DISCUSSION The mechanism by which the liver is pro-tected from preformed antibody states in transplantation is not known. I It has not been clarified whether this reflects the unique architecture of the liver, the distribution of HLA antigens within the liver, or the possibil:" ity that the liver is able to "neutralize" spe-cific antibodies by release of soluble HLA antigens. Starzl and coworkers first demon-strated that sequential liver-kidney trans-plants in presensitized dogs could protect the renal limb from acute rejection.6 This has been subsequently confirmed in the murine mode!.7 The current study demonstrates the ability of sequential liver-kidney transplantation in the prevention of hyperacute renal rejection in a patient with demonstrated preformed anti-HLA lymphocytotoxic antibodies. The dramatic and sustained fall of DLC was tem-porally related to placement of the liver allo-graft. This was most likely due to absorption or neutralization of antibodies by the donor liver, and not by dilutional effects. The applicability of the concept of multior-gan transplantation in transplanting potential presensitized renal transplant candidates is, of course, limited, but the mechanisms of protec-tion using this model, if defined, may provide clues for less drastic therapeutic approaches. REFERENCES I. Iwatsuki S, Iwaki Y, Kano T, et al: Transplant Proc 13:286, J 981 2. Kissmeyer-Nielsen F, Olsen S, Peterson V, et al: Lancet 2:662, 1966 3. Starzl T, Iwatsuki S, Esquivel C, et al: Semin Liver Dis 5:349,1985 4. Starzl T, Marchioro T, Dickinson T, et al: Arch Surg 89:87,1964 5. fung J, Demetris A, Porter K, et al: Nephron (in press) 6. Simpson K, Bunch D, Amemiya H, et al: Surgery 68:77,1970 7. Kamada N, Davies H, Roser B: Nature 292:840, 1981 

Successful sequential liver-kidney transplantation in a patient with preformed lymphocytotoxic antibodies

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Successful sequential liver-kidney transplantation in a patient with preformed lymphocytotoxic antibodies

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