Orthotopic liver transplantation using low-dose tacrolimus and sirolimus.

Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.

Extravesical ureteroneocystostomy with and without internalized ureteric stents in pediatric renal transplantation.

The use of ureteric double-J stents and the Lich-Gregoir (extravesical) technique of ureteroneocystotomy have both been shown to decrease the rate of urologic complications in adult kidney transplantation (Tx). There are, however, few studies of the systematic use of stents in pediatric renal Tx. Between 1991 and 1997, 32 consecutive pediatric renal transplant recipients routinely received a 6F-12 cm indwelling double-J stent and were studied prospectively. These patients were compared with 32 consecutive pediatric recipients in whom a stent was not used. The latter were transplanted between 1987 and 1991 and formed the control group. All patients had a Lich-Gregoir ureteroneocystotomy. Stents were removed under general-anesthetic cystoscopy 2 3 weeks after Tx. Immunosuppression for stented patients was polyclonal antibody induction, delayed (7-10 days) cyclosporin A, azathioprine, and prednisone. The control group received the same triple drug regimen but with no induction in 29 of the 32 patients. All patients were followed-up with at least one ultrasound evaluation in the first month, and a renal scan and repeat ultrasound were performed if there was any rise in serum creatinine. In the stented group there were two patients with urinary leak and no obstructions. In the non-stented group there were no leaks and one obstruction. There was no graft loss owing to urologic complications in either group. There were three cases of stent expulsion (all in girls) and one case of stent migration in the posterior urethra (a boy). The 1-yr graft survival rate was 90.6% in the stented group and 65.6% in the non-stented group. The prophylactic use of an indwelling ureteral stent in pediatric renal Tx did not reduce the risk of urinary leakage or obstruction. Stent migration is a common phenomenon and, while not a serious complication, is traumatic to children. Furthermore, removal of an internalized double-J stent requires a general anesthetic. We recommend using a stent for selected patients only.

Kidney graft loss in children: implications for program development.

BACKGROUND: Graft survival in children who undergo kidney transplantation is lower than that in adults. The objective of the study was to review the experience of the first 22 years of operation of the regional pediatric kidney transplantation unit for Atlantic Canada, based at the IWK-Grace Health Centre, Halifax, and to use the results to improve graft survival. METHODS: All cases of kidney transplantation performed at the centre from 1971 to 1992 were reviewed and the data compiled with the use of a predetermined database outline. Data for first transplants were analysed and compared with those in North American databases. Of the 40 graft failures, 19 (48%) occurred within the first 3 months after transplantation, a rate similar to that at other centres. The overall survival rates tended to be slightly lower than those of international databases. The introduction of cyclosporine A as an immunosuppressant, in 1985, did not provide the expected marked improvement in survival. Infection frequently accompanied acute rejection, and there was a delay in treatment of infections and rejection after discharge home. On the basis of these preliminary findings, several program changes were made: 1) a sequential immunosuppression protocol was implemented, 2) the intensity of the medical surveillance was increased for the first 3 months after transplantation, with aggressive treatment of infections and rejections, 3) a dedicated pediatric transplantation team was established as a subset of the adult team and 4) pediatric-specific selection criteria for cadaver donors were formulated. After these changes were implemented, data were collected and analysed up to June 30, 1997. RESULTS: Graft survival rates at 1, 2 and 5 years improved dramatically. After the beginning of 1993, there were only 2 graft losses among 22 transplants. Only one of these occurred in the first 3 months, and it was due to recurrent disease. Twenty-four rejection episodes occurred (10 in the first 3 months after transplantation), but all were reversed easily with high-dose steroid therapy. INTERPRETATION: Sequential immunosuppression with close medical surveillance and early aggressive treatment of infection and rejection contribute to a marked improvement in kidney graft survival in children.

Infection concomitant with pediatric renal allograft rejection.

Renal allograft rejection episodes are frequent in children and often lead to allograft failure. Frequent association of fever with rejection in our transplant program provoked a prospective evaluation of concurrent infection during rejection episodes. Because cytomegalovirus has an established role in rejection and allograft survival, evaluation of cytomegalovirus and other herpes viruses (human simplex virus type 1, varicella, Epstein-Barr virus, and human herpes virus type 6 [HHV-6]) was undertaken in addition to standard bacterial investigation. A total of 37 patients were followed over a 30-month period. Six of eight rejection episodes were associated with herpes viruses (HHV-6, n = 6, and Epstein-Barr virus, n = 1). Three of the herpes-group-associated rejection episodes were treated with antiviral therapy in addition to pulse steroid treatment, with full recovery. The three patients with HHV-6-associated rejection episodes who were treated with pulse steroids, but no antiviral therapy, developed chronic allograft rejection. The recipient's response to allograft antigens may be influenced by concomitant herpes infection, and specific antiviral therapy appears to be indicated when infection is confirmed in association with rejection. An antiviral treatment program coupled with modulation of standard antirejection immunotherapy has the potential to improve morbidity and mortality in the pediatric renal transplant population.

Importance of minor histocompatibility antigens in the development of allograft arteriosclerosis.

Although acute rejection has been mostly ameliorated with the use of powerful immunosuppressive drugs, kidney and heart transplants continue to succumb to a more chronic response characterized by intimal lesions in the graft vasculature. This late-stage response is referred to as allograft arteriosclerosis. Allorecognition is clearly involved in the initiation of this response but the relative importance of major histocompatibility (MHC) and minor histocompatibility (mH) antigens remains unclear. By taking advantage of the B10 congenic set of mice and our newly described mouse aortic interposition graft model we have been able to assess the contribution of these antigens to the development of the concentric intimal lesions characteristic of allograft arteriosclerosis. We performed transplants between syngeneic animals, animals which were disparate at both MHC and multiple mH, animals which were disparate at MHC only, and animals which were disparate at multiple mH antigens only. H-Y antigen variation was controlled for by performing all transplants between female mice. In all cases the recipients were C57BL/10 (H-2b) mice. Both cellular infiltration into the intima and resulting intimal thickness were measured at 2, 4, 8, and 13 weeks posttransplant. At all time points, the grafts from MHC disparate only donors showed less severe intimal lesions than the grafts from fully disparate or mH disparate donors. This difference reached statistical significance at 4 and 13 weeks. This suggests that mH antigens are as immunogenic as MHC antigens with respect to the generation of allograft arteriosclerosis. These findings are not unique to vascular grafts and may relate to the importance of indirect antigen presentation in the development of chronic rejection.

Kidney transplantation, the Halifax experience.

In the absence of a national kidney sharing system in Canada, virtually all the cadaver kidneys we transplant come from donors within the 4 provinces we serve. Currently the only criteria we use for recipient selection of cadaver kidneys, apart from ABO blood group matching and a negative anti-T-cell crossmatch, are good HLA match and transplant wait-list seniority. All transplant recipients receive CsA-based immunosuppression. Antibody induction is used only for repeat transplants and pediatric transplants. Recipients of first cadaver kidney transplants with zero HLA-DR mismatches have significantly better graft survival than those with mismatches. Graft and patient survival rates for first cadaver transplants continue to improve within the CsA era, and are comparable to those seen in centers routinely using antibody induction and routine sequential quadruple immunosuppression. Chronic graft nephropathy continues to be the most important cause of graft loss after the first year, unchanged over the past 2 decades, followed closely by death with a functioning kidney. The latter is a more important cause of loss in recipients older than age 60, and in recipients of HLA-identical live donor transplants. Repeat cadaver transplant recipients have a 5-year graft survival rate today equivalent to that seen with first cadaver transplants. Graft loss from acute rejection is modest, but kidneys requiring rescue therapy for steroid-resistant rejection have significantly poorer one- and 5-year graft survival and ultimately are lost from rejection. Patients with HLA-identical live-related donor transplants have better long-term survival with CsA than with azathioprine due to a decrease in graft loss from chronic rejection. Pre-transplant sensitization has an adverse effect on graft survival for haploidentical but not HLA identical live-related transplants. Patients over age 60 have equivalent graft survival to younger recipients for at least 7 years, and should not be precluded from receiving transplants by age alone. Prolonged CIT > 24 hours is associated with a significantly increased incidence and duration of ATN and need for dialysis, significantly increased early and late graft loss from acute and chronic rejection respectively, significantly reduced QALY's, and significantly higher early and late costs of transplantation.

Development of a mouse aortic transplant model of chronic rejection.

Chronic rejection is the most common cause of late graft failure after solid organ transplantation. A model of chronic rejection, the rat aortic allograft, has histologic features that parallel those in the vessels of human transplanted organs. However, the molecular tools required to dissect the immunology of chronic rejection are unavailable in the rat. We developed aortic transplantation in the mouse as a new model of chronic rejection. This will allow the use of the diversity of recombinant cytokines and monoclonal antibodies available for the mouse and its well-defined genetics to investigate chronic rejection in greater detail. We describe the perioperative care and surgical technique for the model in which a 1 cm segment of donor thoracic aorta was used to replace a section of recipient abdominal aorta below the renal arteries and above the aortic bifurcation. Mortality rates were initially high (70%) due to thrombosis and shock. Changes in technique and operator facility resulted in a high rate of success (75%). After 192 operations, the current success rate is > 80%. Mice free from complications at 12 hrs postop had indefinite survival, and after 2 months the typical vascular lesion of chronic rejection was present. This new model of chronic rejection will be a valuable tool to study the molecular immunology and genetics of chronic rejection.