Successful Retransplantation Research Articles

Fulminant hepatic failure post liver transplantation: clinical syndromes, correlations and outcomes.

This paper reports the clinical syndrome of fulminant hepatic failure (FHF) following liver transplantation. FHF was defined as the sudden onset of liver failure [encephalopathy and prolonged International Normalised Ratio (INR)] without arterial thrombosis in the setting of a liver allograft. FHf post-transplant was seen in 8/154 (5.2%) adult patients undergoing transplantation. These eight patients developed a clinical syndrome characterised by: (a) a rapid rise in ALT levels to above 1000 U/l (mean maximum 1600 U/l), (b) a sudden increase in the INR to above 5 (mean maximum 5.6), (c) the development of high fever, (d) the persistence of thrombocytopenia (mean nadir 40 x 10(9)/dl), (e) a progressive rise in the bilirubin (mean maximum 400 mumol/l) and (f) the development of hepatic encephalopathy. In seven cases this syndrome occurred following good initial graft function at day 6 post (mean)-transplant. In one case the above syndrome developed immediately after liver transplantation. Four of the eight patients developed multiorgan failure associated with systemic acidosis (mean pH 6.84). All of these patients died (mean day 11). Four patients developed systemic alkalosis. Two of these four patients underwent successful retransplantation (on days 12 and 13) and remain alive at a mean of 11 months post-transplant. Six of the eight patients received OKT3 therapy without any apparent affect on clinical outcome. Compared to control group of patients (n = 28), 8 versus 2/28 had a positive cross-match with donor lymphocytes (P = NS), 1/8 versus 7/28 were ABO-non-identical (P = NS), 3/8 versus 10/21 had total MHC mismatches (P = NS) and 5/7 versus 6/16 had UW ischemic times above 10 h (P = NS). No patients had main hepatic artery thrombosis on angiography although four patients had evidence of intrahepatic microthrombi or arterial necrosis at autopsy. In all cases the histology showed massive haemorrhagic necrosis. Three cases had evidence of veno-occlusive lesions whilst foam cell arteriopathy was seen in two cases. Immunofluorescence was performed in three cases. In two cases there was evidence of immunoglobulin, complement and fibrin deposition in blood vessels. In conclusion, we describe an uncommon clinical syndrome occurring post liver transplant. This syndrome represents humorally mediated allograft rejection but there seems to be no relationship with tissue matching (antibody, ABO, MHC) or donor ischaemic times. If recognised earlier in the absence of multiorgan failure, urgent retransplantation seems to be the only effective therapy.

FK506 conversion therapy in pediatric liver transplantation.

The safety and efficacy of conversion to FK506 after failing immunosuppression with cyclosporine was prospectively evaluated in 31 pediatric liver transplant recipients between April 1991 and March 1993. The patients, who ranged in age from 40 days to 14 years, accounted for 28 primary transplantations and 3 retransplantations. The initial immunosuppression regimen consisted of cyclosporine in combination with prednisone. The indications for conversion were acute or chronic rejection refractory to OKT3, Minnesota antilymphocyte globulin, or steroids (13 patients); hypertension (8 patients); inability to reach a therapeutic level of cyclosporine (6 patients); hirsutism (3 patients); and growth retardation (1 patient). After an average follow-up of 10 months (range, 2 to 25 months), 27 (87%) of the patients are alive and have functioning grafts. Of the 13 patients who were converted for refractory rejection, 9 are alive. Six of these 9 patients experienced a complete biochemical reversal of the rejection process within 3 months of conversion; 2 had a partial response to conversion, and 1 patient failed but underwent successful retransplantation. Three of the 4 patients who died did so without showing any improvement. The remaining 18 patients who were converted for various other reasons are alive and have functioning grafts. Of the 8 patients who developed hypertension on cyclosporine and prednisone, 6 experienced a resolution of this problem within 3 months of conversion. Three of the 18 children who underwent rescue therapy for reasons other than refractory rejection experienced rejection episodes after conversion to FK506. Two of these 3 children achieved resolution with either steroid therapy or an increased dosage of FK506, while the third child developed chronic rejection. The side effects of FK506 were generally minor and resolved by lowering the dose. Lymphoproliferative disease developed in 2 patients (6%). The present study suggests that FK506 is a relatively safe and effective rescue therapy for pediatric liver transplant recipients who have failed immunosuppression with cyclosporine. Longer follow-up is needed to assess the effect of FK506 on growth.

RETRANSPLANTATION IN MINIATURE SWINE

In miniature swine, one-haplotype class I disparate renal allografts are accepted without exogenous immunosuppression by approximately 35% of recipients. Alternatively, transplants bearing a two-haplotype class I mismatch are always rejected acutely. However, long-term acceptance in the latter animals can be achieved uniformly with a 12-day course of cyclosporine. In vitro studies of recipient cell-mediated lymphocytotoxicity responses have shown donor-specific cytotoxic T lymphocyte clones in tolerant animals, suggesting that tolerance may be a local phenomenon or a central phenomenon activated in the milieu of the graft. Six animals were retransplanted with kidneys MHC-matched to their original allograft to determine whether (1) tolerance is a central phenomenon; (2) host tolerance can be broken with a fresh challenge of donor antigen and antigen-presenting cells; and (3) graft adaptation is required for maintenance of tolerance. Four of the retransplanted animals had been spontaneous acceptors of one-haplotype class I-disparate grafts and two had been rendered tolerant to two-haplotype class I-mismatched kidneys with CsA induction. All six explanted allografts showed no histological evidence of rejection and all six retransplants were accepted without exogenous immunosuppression. These findings suggest that in miniature swine tolerance of class I-disparate kidneys is a stable, centrally mediated phenomenon that cannot be broken with a challenge of fresh donor antigen and donor-type APCs. Furthermore, successful retransplantation without immunosuppression in animals receiving CsA induction therapy for their first transplant suggests that graft adaptation is not necessary for the maintenance of tolerance.

INTRAVENOUS IMMUNOGLOBULIN SUPPRESSION OF HLA ALLOANTIBODY IN HIGHLY SENSITIZED TRANSPLANT CANDIDATES AND TRANSPLANTATION WITH A HISTOINCOMPATIBLE ORGAN

Patients awaiting solid organ transplantation who are highly sensitized to HLA antigens remain problematic in terms of finding compatible (crossmatch-negative) donors. We have used intravenous gammaglobulin (IVIG; 10% Gamimune N) to determine both its efficacy in reducing panel-reactive antibodies in vitro and the prognostic value of the in vitro testing for in vivo efficacy. In 18 patients with PRAs ranging from 40 to 100% (mean: 77%) we found a reduction in absolute PRA of 4-70% (mean decrease: 35%; percent inhibition: 4-100%; residual PRA 0-96%). In 7 cases, the residual antibody specificity could be easily determined and often appeared to include a short HLA-A2. This was independent of A2 subtype as determined by PCR-SSOP. Testing the IVIG on a panel of 21 HLA reagent alloantisera resulted in heterogeneous inhibitory patterns (7 complete, 3 partial, 8 differential, 3 none) independent of titer or specificity. In vivo administration to a 13-year-old kidney patient awaiting retransplant resulted in a PRA drop from 95% to 15% and successful retransplantation (now 11 months post-transplant). More impressively, successive in vivo administration of IVIG to a sensitized (anti-HLA-A2, A68, A69; B57, B58) heart transplant candidate resulted in successful transplantation with an A2+ histoincompatible heart. The patient experienced only one subclinical humoral rejection in the first 5 months posttransplant. Biochemical studies to determine the effective component of IVIG show that it is the IgG fraction and not soluble antigen or the minor IgM or IgA contaminants that is responsible. This suggests an antiidiotypic modulation of anti-HLA antibodies in vitro and in vivo.

Successful Retransplantation of the Heart and Lungs in an Adult with Cystic Fibrosis

Successful Retransplantation of the Heart and Lungs in an Adult with Cystic Fibrosis

A Prospective Study on the Use of Monoclonal Anti—T3-Cell Antibody (OKT3) to Treat Steroid-Resistant Liver Transplant Rejection

Conventional treatment of acute liver allograft rejection has included high doses of corticosteroids and antithymocyte globulin. Urgent retransplantation was the only option for patients who failed to respond. We report our initial experience with the use of monoclonal anti-T3-cell antibody (OKT3) in 25 patients with acute hepatic allograft rejection that was resistant to steroid and/or antithymocyte globulin therapy. Twenty-four of 25 patients had a response to OKT3, which was complete in 14 and partial in ten. With a mean follow-up of 8.2 months, allograft salvage has been 80% and patient survival 88%; two patients underwent successful retransplantation. Side effects have been mild and well tolerated. Repeated rejection has occurred in 40% of patients, but these episodes have responded to steroid therapy. We conclude that OKT3 is well tolerated and highly effective in reversing severe episodes of acute hepatic allograft rejection that is resistant to high-dose steroid therapy.

Successful allogeneic bone marrow retransplantation with the same donor after graft rejection: Application of a modified conditioning regimen

A 26-year-old man with severe aplastic anemia was treated with high-dose Cyclophosphamide followed by the infusion of bone marrow cells from his HLA-identical sister. After initial intake of the graft, rejection ensued by day 46 which was followed by a permanent complete aplasia. After 4 months, bone marrow retransplantation with the same donor was attempted after a more intensive conditioning regimen. This led to permanent engraftment with rapid normalization of the blood counts lasting now for over 12 months. The patient has since remained in excellent clinical condition without signs of graft-versus-host disease.

Renal Allograft Rupture

In the present material of 448 consecutive renal transplants the incidence of allograft rupture was 3.6%. Among 389 first transplants there were two ruptures in the living donor group (126 patients, 1.5%) and 12 ruptures in the cadaveric donor group (263 patients, 4.6%). Only one ruptured kidney (living donor) achieved long term function. Four patients with first graft rupture were retransplanted with early loss of the kidney in all, in two because of rupture. Two of these patients received a 3rd cadaveric graft, of which one is functioning well after two years. All ruptures occurred within three weeks after transplantation, 14 kidneys ruptured during the first week. The clinical course and the operative findings suggested that rejection was the cause of rupture in all cases. This was confirmed by light and immunofluorescent microscopy of specimens from 15 kidneys, while one kidney only demonstrated extensive intrarenal vessel thrombosis. It is concluded that renal allograft rupture signals a strong immunological response in the recipient with poor graft prognosis. The chance of a successful retransplantation is small.

Successful retransplantation of bone marrow following failure of initial engraftment in a patient with aplastic anemia

Histobompatible sibling bone marrow was transplanted to a patient withsevere aplastic anemia. The first transplant failed, but a second transplantfrom the same donor was successfully performed with a new and more potentimmunosuppressive regimen. Successful retransplantation after marrow graftrejection is now possible.

RENAL HOMOTRANSPLANTATION IN PEDIATRIC PATIENTS

Fifty-seven patients were treated with renal homotransplantation from 1½ to 7⅔ years ago; 23 patients were 12 years or younger and the other 34 patients were 13 to 18. Family members (usually parents) were the primary donors in 45 cases. Unrelated volunteers or cadavers donated the other 12 homografts. Immunosuppression was with azathioprine and prednisone, and in some cases also with ALG. Forty-two of the 57 recipients survived for at least 1 year. Additional deaths occurred at 17½ and 19 months leaving 40 recipients (70.2%) alive. Six survivors had successful retransplantation following late failure of their original homografts. Control of rejection was not particularly different than in adult cases. "Homograft glomerulonephritis" was found in chronically tolerated transplants, but no more frequently than in older patients. Many postoperative problems in the pediatric age group were the consequence of retardation of growth caused either by pre-existing uremia or by the need for high dose postoperative steroid therapy, orthopedic accidents such as femoral and vertebral fractures, and psychiatric complications which led to two suicides. In spite of these difficulties, the meaningful rehabilitation that was obtained in the chronic survivors makes us regard pediatric patients as favorable candidates for therapy with renal transplantation.