Outcomes with the selective use of enteric exocrine drainage in pancreas transplantation.

BACKGROUND: Bladder drainage of the exocrine secretions of pancreas transplants has been the standard of practice as it affords the ability to monitor for rejection and is thought to be associated with decreased morbidity. Recently, there has been renewed interest in avoiding the urinary tract complications and metabolic derangements that accompany bladder drainage by draining pancreatic exocrine secretions into the jejunum (enteric drainage). We sought to determine whether enteric drainage of pancreas transplants is safe and offers advantages without compromise in graft function or longevity. METHODS: We retrospectively reviewed all pancreas transplants performed at the University of Washington between 2000 and 2003. Selection of the exocrine drainage method was based on the length of cold ischemia time and whether the pancreas was transplanted alone or in combination with a kidney. Pearson's chi-square and Fisher's Exact tests were used for statistical comparisons in complications or rejections between the groups. RESULTS: Thirty-four pancreas transplants were performed with exocrine drainage into the bladder used in 17 and enteric drainage in 17. The complication rate was 53% in the bladder-drained group and 41% (P=.49) in the enteric-drained group. The incidence of pancreas rejection was 24% in the bladder-drained versus 29% in the enteric-drained patients (P=.50). One graft failed, which was in the bladder cohort. CONCLUSIONS: We found comparable rejection and complication rates between groups. We conclude that enteric drainage is safe when used selectively, and entails no increased risks compared with bladder drainage.

Rescue of acute portal vein thrombosis after liver transplantation using a cavoportal shunt at re-transplantation.

BACKGROUND: Portal vein thrombosis is a rare but devastating complication following orthotopic liver transplantation. Fulminant liver failure ensues with acute portal vein thrombosis after transplantation limiting the treatment options. METHODS: We successfully re-transplanted a 46-year-old female patient who developed acute portal vein thrombosis 19 d after orthotopic liver transplantation. Vascular reconstruction included a cavoportal shunt to augment portal blood flow. RESULTS: Twelve months after re-transplantation this patient lives independently and enjoys excellent liver allograft function. CONCLUSIONS: Cavoportal shunt can augment portal blood flow in adult recipients of orthotopic liver transplants. This technique can be successfully employed during re-transplantation when portal blood flow is inadequate to maintain patency.

Venous thrombosis and occlusion after pancreas transplantation: evaluation with breath-hold gadolinium-enhanced three-dimensional MR imaging.

OBJECTIVE: We describe the imaging findings of venous thrombosis and occlusion after pancreatic transplantation in five patients who underwent multiphasic breath-hold gadolinium-enhanced three-dimensional MR imaging. CONCLUSION: Venous thrombus appeared as serpetine voids within the graft parenchyma or at the venous anastomosis during the venous phase of MR imaging. Nonenhancement or heterogeneous enhancement of graft parenchyma corresponded to glandular necrosis at pancreatectomy in two patients. Initial sonographic evaluation was nondiagnostic of venous thrombosis in two of five patients. Multiphasic breath-hold gadolinium-enhanced three-dimensional MR imaging of pancreatic transplants can provide information to make the specific diagnosis of venous thrombosis or occlusion.

A strategy for generating consistent long-term donor-specific tolerance to solid organ allografts.

Current triple drug immunosuppression while effective, increases the risk of opportunistic infection and lymphoproliferative disorders. An alternative strategy would be the generation of donor-specific tolerance with short-term treatment. The use of donor-specific transfusions (DST) with a single brief course of cyclosporine (CsA) and rapamycin (Rapa) has produced promising results in animal models, but falls short of uniform tolerance. It was hypothesized that a DST/CsA/Rapa protocol administered in the perioperative period and redosed at one month might improve on this success in the ACI to Lewis rat heterotopic cardiac transplant model. Recipients received no treatment (group 1), a 1 ml DST intravenously (i.v.) with CsA 10 mg/kg subcutaneously (s.c.) at D-1 and CsA 2.5 mg/kg DO6D+13 (group 2), DST/CsA as dosed above with intraperitoneally (i.p.) Rapa 1 mg/kg D+36D+7 (group 3), DST/CsA/Rapa as above with all components redosed at one month (group 4), DST/CsA/Rapa with only CsA and Rapa repeated (group 5), and DST/CsA/Rapa with CsA redosed and Rapa continued indefinitely (group 6). Comparison of permanent survival (longer than 200 days) between protocols revealed groups 4-6 were significantly greater than control groups 1-3. Donor specificity was verified in group 6, where three permanent survivors received a second cardiac allograft from a Buffalo rat donor and rejected these grafts almost as quickly as untreated strain pair matched controls 21 +/- 1 days vs 30.3 +/- 5 days. Animals from group 6 displayed a greatly reduced mixed lymphocyte response to ACI cells but not to third-party cells. The percentage of T cells producing cytokines was reduced and shifted toward Th-2 type cytokines (IL-4). Thus, a repeated cycle of this brief DST/CsA/Rapa treatment appears to generate consistent permanent graft survival (up to 91%) that exceeds previously studied tolerance inducation protocols and is donor specific.

An examination of tissue chimerism in the ACI to Lewis rat cardiac transplant model.

While the existence of chimeric cells in host tissue following organ transplantation is well documented, its distribution, temporal evolution and relationship to allograft survival is less clear. To explore this phenomenon, Lewis recipients of ACI cardiac allografts representing a wide range of immunosuppressive protocols and graft survival times were examined for the presence of chimerism using a sensitive polymerase chain reaction assay. Four groups of animals were examined: untransplanted animals receiving donor specific transfusion (DST)/cyclosporine A (CsA); allograft recipients with no treatment; recipients treated with DST/CsA/supplementary immunosuppression with rejection at 21-183 days; and recipients sacrificed with functioning allografts, treated with DST/CsA/supplementary immunosuppression and surviving > 200 days. To elucidate variations in the tissue distribution of chimeric cells, bone marrow, skin, liver, spleen, and thymus were examined in each animal. Untransplanted animals receiving DST/CsA displayed no evidence of chimerism. In animals receiving a cardiac allograft but no treatment, there was extensive evidence of chimerism in four of five animals. Chimerism was also detected in seven of nine animals with intermediate graft survival at the time of rejection. In animals with long-term graft survival, only four of eight displayed chimerism. These results suggest that, without immunosuppression, early chimerism does not lead to prolonged graft survival and that, even when graft survival is moderately prolonged, these cells are not sufficient to prevent rejection. In conclusion, chimerism appears to be a common phenomenon following transplantation, is not a result of DST, and may not be necessary for maintenance of long-term graft survival.

The significance of timing of additional short-term immunosuppression in the donor-specific transfusion/cyclosporine-treated rat.

It is hypothesized that the mechanism, or mechanisms, responsible for donor-specific transfusion (DST)/cyclosporine (CsA) immunosuppression is generated by an active immune response that is most dynamic in the immediate peritransplant period and thus might be at the peak of vulnerability to the influences of added immunosuppression. To better define this concept, four immunosuppressive drugs were combined with a d-1 DST and 14-day course of CsA in the ACl-to-Lewis cardiac transplant model. A 5-day course of antithymocyte globulin (ATG) initiated at d-1 or d+4 with DST/CsA reduced survival vs. DST/CsA alone (27.0 +/- 2.6 days and 24.6 +/- 5.7 days vs. 95.3 +/- 16.3 days, P<.05). Delay of initiation to d+7 improved survival to 39.5 +/- 8.9 days. A 5-day course of methylprednisolone (MP) begun at d-1 with DST/CsA decreased survival vs. DST/CsA alone, 59.2 +/- l0.0 days vs. 95.3 +/- 16.3 days, but delay to d+4 improved survival to 110 +/- l8 days, P<.05 vs d-1. A 3-day course of brequinar (Breq) begun at d-1 with DST/CsA increased survival to 244 +/- 48.6 days, while delay to d+4 reduced survival to 49.0 +/- 6.7 days, P<.05 vs. d-1. Finally, a 5-day course of rapamycin (Rapa), was given with d-1 DST/CsA treatment beginning on d-1, d0, d+l, d+3, d+5, and d+7. In this instance, no significant differences in survival were found between timing groups or DST/CsA control. Together, these data support the hypothesis that DST/CsA treatment generates an active immune response that is inhibited by early initiation of ATG or MP, enhanced by early administration of Breq, and unchanged by early administration of Rapa.

Nutritional immunomodulation enhances cardiac allograft survival in rats treated with donor-specific transfusion and cyclosporine.

The aim of this study was to assess the efficacy of an enteral diet fortified with arginine, RNA, and fish oil (Impact), alone and in combination with cyclosporine (CsA) and donor-specific transfusion (DST) on allograft survival in the ACI:Lewis rat cardiac transplant model. Animals were fed ad libitum with either standard rat chow or Impact diet. Six groups were studied; these consisted of untreated recipients fed either standard diet or Impact diet; recipients treated with CsA 10 mg/kg on the day prior to engraftment (day-1) followed by 2.5 mg/kg/d, day 0-->day+13 and fed with either standard diet or Impact; and animals given a DST (1 ml) on day-1, CsA as described previously and fed either standard diet or Impact. Untreated animals standard diet (group 1, n = 8) rejected their allografts at 7.0 +/- 0.0 days, while those fed Impact (group 2, n = 9) had graft survival of 12.8 +/- 2.1 days, (P = .01 versus group 1). Animals treated with CsA alone and standard diet (group 3, n = 9) rejected at 30.3 +/- 4.8 days, while the combination of CsA and Impact diet (group 4, n = 8) rejected at 33.0 +/- 9.5 days--minimally improved survival compared with group 3. Animals treated with DST/CsA and standard diet (group 5, n = 7) rejected at 72.1 +/- 6.8 days, while the substitution of Impact for standard diet (group 6, n = 8) led to a significant graft prolongation to 275 +/- 53 days, n = 8 (P < .015 vs. groups 1-5). These data suggest that Impact diet alone can have potent immunomodulatory properties but may require the addition of DST/CsA to realize its potential. These findings underscore the potential of dietary immunomodulatory therapy to prevent rejection and promote tolerance to solid organ allografts.

Administration of intragraft interleukin-4 prolongs cardiac allograft survival in rats treated with donor-specific transfusion/cyclosporine.

It has been hypothesized that immunoregulating cytokines produced by intragraft Th-2 cells may be important for prolonged allograft survival. ACI hearts transplanted into untreated Lewis rat recipients survived for 6.2 days, but they survived for 72.1 days in recipients treated with a donor-specific transfusion and low dose CsA for 14 days. In donor-specific transfusion/CsA-treated animals, intragraft infusion of IL-10 via a 14-day osmotic minipump had no effect on graft survival (75.6 days), but intragraft infusion of IL-4 prolonged graft survival to 149.2 days (P < 0.01). While the actual mechanism of this effect is unclear, it suggests that IL-4 may be important in the development of long-term graft survival.