Evidence that pediatric liver transplant recipients may undergo late rejection episodes in spite of donor-specific microchimerism.

Lymphocytes of donor origin can be demonstrated in the blood of many liver transplant recipients. It has been proposed that this chimerism may imply graft tolerance and permit withdrawal of immunosuppression. We report two children with liver transplants who had lymphocyte chimerism demonstrated at the time of late rejection episodes. One child was chimeric for both of his donors, although he retained the first allograft for only 3 days. Thus, the persistence of donor lymphocytes may be unrelated to the presence of the donor organ. Graft rejection can occur in spite of donor-specific microchimerism. The role of donor-specific microchimerism in graft acceptance or graft tolerance remains to be elucidated.

Renal transplantation one week after conception.

A successful 38-week pregnancy is reported following renal transplantation approximately 1 week after conception. The patient was treated with quadruple sequential induction therapy, maintenance immunosuppression, and routine posttransplantation care, including ganciclovir treatment for a symptomatic cytomegalovirus infection during the pregnancy and 3 months after delivery. No decline in renal function was noted. The mother and child remain healthy at 18 months. This case demonstrates the ability of renal transplant patients to maintain renal function throughout pregnancy and the lack of deleterious effects upon the child during gestation and at up to 18 months after birth, despite significant immunosuppression, including antithymocyte globulin induction therapy, and infectious complications of the mother's renal transplantation.

Cadaveric versus living donor kidney transplantation: a Medicare payment analysis.

BACKGROUND: We found previously that the clinical advantages of living donor (LD) renal transplantation lead to financial cost savings compared to either cadaveric donation (CAD) or dialysis. Here, we analyze the sources of the cost savings of LD versus CAD kidney transplantation. METHODS: We used United States Renal Data System data to merge United Network for Organ Sharing registry information with Medicare claims data for 1991-1996. Information was available for 42,868 CAD and 13,754 LD transplants. More than 5 million Medicare payment records were analyzed. We calculated the difference in average payments made by Medicare for CAD and LD for services provided during the first posttransplant year. RESULTS: Average total payments were $39,534 and $24,652 for CAD and LD, respectively (P<0.0001) during the first posttransplant year. The largest source of the difference in payments was in inpatient hospitals, representing $10,653.67 (P<0.0001). For patients who had Medicare as the primary payer, average transplant charges were significantly higher for CAD donation ($79,730 vs. $69,547, P<0.0001); average transplant payments demonstrated no statistical differences ($28,483 vs. $28,447, P = 0.858). Therefore, inferred profitability was significantly higher for LD. CONCLUSIONS: Medicare payments are remarkably lower for LD compared to CAD in every category. The single largest cost saving comes from inpatient hospital services. A portion of the savings from LD could be invested in programs to expand living kidney donation.

A comparison of UW with Eurocollins preservation solution in liver transplantation.

Fifty consecutive liver transplants were performed using livers perfused with and stored in University of Wisconsin preservation solution. These grafts were compared with the preceding 55 consecutive transplants performed using livers perfused and preserved with Eurocollins solution. The purpose of the study was to determine if organs preserved with UW solution functioned better after transplantation than organs preserved with Eurocollins. Extensive retrospective analysis of prospectively accumulated data included enzyme levels through 30 days, cost and length of hospital stay, blood product usage, and ischemia time. Average age of patients in the UW group was 47.1 years compared with 39.6 years in the EC group (P less than 0.05); cold ischemia time was 7.21 hr in the UW group compared with 5.21 in EC (P = 0.0001). Total bilirubin values were significantly lower on days 0-6 and day 14, but not day 30, in the UW group. Aspartate aminotransferase was significantly lower in the UW group on days 0-1, 3-6, and 14, but not on day 3 or day 30. Prothrombin times were significantly lower in the UW group across all times (days 0-6, 14, and 30). Intraoperative and postoperative use of packed red blood cells and fresh frozen plasma was lower in the UW group (P less than or equal to .05). Also, total hospital days, intensive care unit days, and hospital cost to the patient were lower in the UW group (P less than or equal to .05). A second analysis was done comparing only nonemergent transplants from both groups. These results confirmed the initial analysis of a longer cold ischemia time in the UW group (P less than 0.001), and improved enzyme values in the TBR, AST, and PT in the UW group (P less than 0.05). Also, hospital cost in the UW group was again lower (P less than 0.05). In this nonrandomized study, the cold ischemia time was increased but kept close to that of the control group. We conclude that UW solution is an improved donor liver preservation solution on the basis of improved enzyme values, decreased blood usage, shorter hospital stay, and lower hospital charges.

The influence of preservation injury on rejection in the hepatic transplant recipient.

The records of 215 liver transplant recipients were reviewed and the degree of preservation injury was estimated by the initial aminotransferase levels. This was compared with the incidence of rejection found in the subsequent 30 days. Those with aspartate aminotransferase greater than 2000 U/L were classified as having severe preservation injury while those with ASAT less than 600 U/L were considered to have had minimal preservation injury. There were no significant differences between these groups in recipient age, sex, cold ischemia time, preoperative physical status, panel-reactive antibodies, or cytotoxic crossmatch. The solution used for organ preservation and the donor age were the only factors that were found to be significantly different between the groups. Older donors were more common in the severe preservation injury group. Severe preservation injury was found more frequently in grafts preserved in Eurocollins solution and the group with minimal preservation injury more frequently used Wisconsin solution. There was significantly more rejection seen in the severe preservation injury group (71%) than in the group without preservation injury (33%). Although there was more rejection in the severe preservation injury group, the rejections were not more severe as judged by the need for multiple courses of therapy or the need for OKT3. Recurrent rejection was also not more frequent in either group. Graft survival was worse in the severe preservation injury group, with a significant increase in early graft loss, but no difference in the frequency of chronic rejection. Recovery of graft function was also delayed in the preservation injury group.

The economic benefit of allocation of kidneys based on cross-reactive group matching.

BACKGROUND: Recently the United Network for Organ Sharing (UNOS) began a pilot study to evaluate prospectively the merits of an allocation of cadaveric kidneys based on broader classes of HLA antigens, called cross-reactive groups (CREG). The objectives of the pilot study consider patient outcomes, but not the potential economic impact of a CREG-based allocation. This study predicts the impact of a CREG-based local allocation of cadaveric kidneys on 3-year Medicare payments and graft survival. METHODS: The UNOS renal transplant registry was merged to Medicare claims data for 1991-1997 by the United States Renal Data System. Average accumulated Medicare payments and graft survival up to 3 years posttransplant for first cadaveric renal transplant recipients were stratified by cross-reactive group mismatch categories. The economic impact was defined as the difference in average 3-year costs per transplant between the current and proposed allocation algorithms. Average 3-year costs were computed as a weighted average of costs, where the weights were the actual and predicted distributions of transplants across cross-reactive group categories. RESULTS: Results suggest that an organ allocation based on cross-reactive group matching criteria would result in a 3-year cost savings of $1,231 (2%) per transplant, and an average 3-year graft survival improvement of 0.6%. CONCLUSIONS: Cost savings and graft survival improvements can be expected if CREG criteria were to replace current criteria in the current allocation policy for cadaveric kidneys, although the savings appear to be smaller than may be achievable through expanded HLA matching.

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.

BACKGROUND: The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients. METHODS: Transplant recipients (n=72) were randomized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 1.5 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraoperatively, then daily for at least 6 days. Recipients were observed for at least 1 year of follow-up. RESULTS: By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0.014). The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=0.09; P=0.009). Rejection was less severe with Thymoglobulin than Atgam (P=0.02). No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS). Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the "event-free survival," was superior with Thymoglobulin (94%) compared with Atgam (63%; P=0.0005). Fewer adverse events occurred with Thymoglobulin (P=0.013). Leukopenia was more common with Thymoglobulin than Atgam (56% vs. 4%; P<0.0001) during induction. The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0.007), but with Atgam, significant lymphocyte reductions occurred only at day 7. The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs. 33%; P=0.025). CONCLUSIONS: Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam. These results may in fact be explained by a more profound and durable beneficial lymphopenia.

Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients.

BACKGROUND: Treatment with prophylactic oral acyclovir, intravenous ganciclovir, or immunoglobulins to prevent cytomegalovirus (CMV) infection and disease in renal transplantation is associated with variable efficacy and significant expense. We studied control of CMV in renal transplant recipients using either prophylactic oral ganciclovir or deferred therapy with intensive monitoring with polymerase chain reaction (PCR) analysis. METHODS: Forty-two recipients were followed for 6 months after transplantation. Ganciclovir (1000 mg p.o. t.i.d.; n=19) or acyclovir (200 mg p.o. b.i.d.; n=23) was begun at transplantation and continued for 12 weeks. PCR for CMV was performed on buffy-coat specimens every week for 15 weeks and at months 5 and 6. RESULTS: No patients in the ganciclovir group, compared with 14 of 23 patients (61%) in the deferred-therapy group (P<0.0001), developed CMV disease during the first 12 weeks. In the ganciclovir group, 4 of 19 patients (21%) subsequently experienced 5 episodes, whereas 14 patients in the deferred-therapy group experienced 18 episodes (P=0.013 for subjects and P=0.026 for episodes). The time to disease was also delayed in the ganciclovir group compared with the deferred-therapy group (133+/-17 days vs. 51+/-7 days; P<0.0001). Oral ganciclovir also prevented CMV viremia during prophylaxis (2/19 patients [11%] vs. 23/23 patients [100%]). Time to CMV viremia was delayed in the ganciclovir group; however, 13/19 patients (68%) ultimately showed PCR evidence for CMV viremia (P=0.005). CONCLUSIONS: An initial 12-week course of oral ganciclovir prevents CMV disease and infection in renal transplant recipients during prophylaxis, and the benefits persist after discontinuation.

Improved method for the isolation and purification of human islets of langerhans using Liberase enzyme blend.

To determine the effects of procedural modifications, 23 human islet isolations were analyzed. Isolations were divided into two groups based on the enzyme used. The influence of Liberase, with an improved method of mechanical disassociation of pancreas, was compared to an automated method using Sevac collagenase. Pancreases were processed within 10 h of cross clamping. Following ductal injection of the enzyme, tissue was placed in the digestion chamber for disassociation. Purification was accomplished using a COBE 2991 cell processor and continuous gradients of 1Hypaque EuroFicoll. Isolations in Group I (Sevac) had an average yield of 138,602 +/- 128,364 islet equivalents (IE) (2083 +/- 1679 IE/g) with a purity of 85 +/- 11%. Group II (Liberase) showed an average yield of 389,586 +/- 191,161 IE (5,958 +/- 3,083 IE/g) with a purity of 90 +/- 6.8%. Viability was confirmed by fluorescein diacetate and propidium iodide staining, static incubations, and perifusions. In conclusion, the combination of the enzyme blend, Liberase, and a more gentle system of disassociation has proven to be a more productive method of islet isolation with higher purity than the previously published methods.

Cytolytic T lymphocytes from human renal allograft biopsies are tissue specific.

The cytolytic activity of T lymphocytes infiltrating renal allografts from recipients undergoing episodes of acute cellular rejection was studied. These T-cell populations, composed of both CD4+ and CD8+ cells, demonstrated significant cytolytic activity against both donor-derived KCLs and B-LCLs. In five of 21 biopsy-derived lines greater cytolytic activity was measured against donor KCLs compared to donor B-LCLs, suggesting the presence of kidney antigen-specific, MHC-restricted clones. Clones developed by stimulation with donor B-LCLs lysed both donor B-LCLs and KCLs while clones developed on donor KCLs as stimulator cells showed tissue specificity. Three of 26 clones recognized tissue-specific antigens in the context of donor MHC class I antigens lysing donor KCLs but not B-LCLs. These data demonstrate that a subpopulation of T cells recognizing kidney-specific antigens are present in biopsies of renal allograft recipients undergoing acute cellular rejection. This subpopulation of tissue-specific cytotoxic T lymphocytes may prove to contribute significantly to the pathology of allograft rejection.

Problematic vascular reconstruction in liver transplantation. Part II. Portovenous conduits.

Eight of 265 orthotopic liver transplant procedures performed at this institution since December 1984 have used venous conduits to reconstruct an occluded portal system and supply portal blood to the allograft. The factors mandating the use of these conduits were variable, and several reconstructive techniques were used. We present a series of patients with various conditions in which portal conduits were indicated and describe and illustrate the inherent technical considerations.

Living-unrelated renal transplantation provides comparable results to living-related renal transplantation: a 12-year single-center experience.

BACKGROUND: The increasing success of renal transplantation is paralleled by the increased size of the waiting list. Efforts to increase the donor pool have included the use of living-unrelated kidney donors (LURDs). METHODS: During a 12-year period our center performed 309 transplantation from living donors; 279 patients received living-related donor (LRD) transplants, and 30 patients received LURD transplants. During the same period 543 patients received cadaveric renal donor transplants. A total of 86.7% of LURD transplants were spousal transplants. A total of 29% of the patients who received LRDs were human leukocyte antigen-identical with their donors and 53% were haploidentical, versus 0 human leukocyte antigen-identical or haploidentical in the LURD group. RESULTS: Twenty-seven (90%) Of 30 LURD recipients are alive, as are 240 (86%) of 279 LRD recipients. Mean current creatinine is 1.6 mg/dl for the LURD group and 1.7 mg/dl for the LRD group Kaplan-Meier 1- and 5-year graft survival was 94.9% and 82.9% for the LRD group, 93.1% and 85.9% for the LURD group (p = not significant), and 84.6% and 70.7% for the cadaveric renal donor group (p < 0.05). CONCLUSIONS: LURD patient and graft survival is comparable to LRD transplants despite inferior human leukocyte antigen matching. LURD transplant survival is superior to that of cadaveric renal donor transplants. LURDs are an excellent but underused source of organs for renal transplant recipients.

Insulin-like growth factor-I attenuates delayed graft function in a canine renal autotransplantation model.

BACKGROUND: Insulin-like growth factor-I (IGF-I) has been shown to accelerate recovery in animal models of ischemic or toxic acute renal injury. Ischemic renal injury is frequently encountered after cadaveric transplantation manifested as delayed graft function. This study was performed to determine whether perfusion of kidneys with preservation solution supplemented with IGF-I would improve the course of renal injury in a canine autotransplantation model of delayed graft function. METHODS: Dogs underwent unilateral nephrectomy with kidneys perfused and stored in Euro-Collins solution supplemented with vehicle (n = 11) or IGF-I (n = 8). After 24 hours of kidney preservation, a contralateral nephrectomy was performed and the stored kidney was autotransplanted. Renal function was examined for 5 days after the transplantation, and an inulin clearance was obtained at the time of death. RESULTS: Compared with dogs that received kidneys preserved in the vehicle, dogs receiving the IGF-I preserved kidneys had significantly lower daily serum creatinine and blood urea nitrogen levels during the course of 5 days after transplantation. Inulin clearance at death was nearly double in the IGF-I treated animals compared with the vehicle-treated controls (1.37 +/- 0.16 ml/min/kg versus 0.77 +/- 0.13 ml/min/kg; p < 0.05). CONCLUSIONS: Perfusion and storage of kidneys with preservation solution supplemented with IGF-I can attenuate the course of delayed graft function in a canine renal autotransplantation model. IGF-I may have potential for use in cadaveric human renal transplantation.

Hepatic transplantation in a patient with mesoatrial shunt and occlusion of the inferior vena cava.

Occlusion of the vena cava has long been considered an insurmountable difficulty in patients needing liver transplantation. We report the case of a patient with a patent mesoatrial shunt and complete vena cava obstruction who underwent liver transplantation.

Liver transplantation after jejunoileal bypass for morbid obesity.

BACKGROUND: Jejunoileal (JI) bypass was developed as a therapy for morbid obesity in the late 1960s but has since been abandoned because of a high rate of complications, including cirrhosis. The need for liver transplantation after JI bypass has been infrequent, with only four previous patients reported in the literature; however, because the time to develop symptomatic end-stage liver disease after JI bypass may be quite long (25 years or more), the incidence of patients who will require liver transplantation may only now be increasing. STUDY DESIGN: We reviewed our experience with JI bypass and liver transplantation in 380 consecutive adult patients since 1985. RESULTS: Four patients underwent liver transplantation for cirrhosis after JI bypass, all within the last 48 months. The mean duration of time from JI bypass to transplantation was 22.3 years. All patients had complications, in addition to their liver disease, which were related to the JI bypass, which included nephrolithiasis, cholelithiasis, vitamin deficiencies, renal insufficiency, and d-lactic acidosis. One patient had the JI bypass taken down before transplantation, which precipitated acute liver and renal failure, necessitating urgent transplantation. One patient, who had the JI bypass taken down at the time of transplant, has developed recurrent morbid obesity, while the other three patients have not. The one patient who has not had the JI bypass taken down has not developed evidence of recurrent liver disease and is followed with monthly liver function tests and yearly biopsies. CONCLUSIONS: The incidence of patients who require liver transplantation after JI bypass may be on the increase. Take down of the JI bypass may precipitate acute liver failure in the cirrhotic patient. JI bypass should be accomplished either at the time of transplantation or if signs of liver dysfunction occur after transplantation. Liver transplant recipients can be at risk for recurrent obesity after takedown of the JI bypass. Transplantation for those patients with decompensated cirrhosis after JI bypass has demonstrated excellent early results.

Comparison of survival of an expanded polytetrafluoroethylene graft designed for early cannulation to standard wall polytetrafluoroethylene grafts.

BACKGROUND: Placement and maintenance of a well-functioning vascular access are essential for delivery of adequate hemodialysis. Newly placed polytetrafluoroethylene (PTFE) arteriovenous grafts require a period of wound healing and incorporation of fibrous tissue before use, a period typically lasting two to three weeks. An ideal PTFE graft would be one that can be used for vascular access immediately, obviating the need for temporary dialysis catheters. Recently an expanded PTFE (ePTFE) graft with a mesh cannulation segment (Diastat graft) has been proposed for early cannulation. STUDY DESIGN: This is a retrospective single-center study comparing ePTFE graft survival to contemporaneously placed standard wall PTFE (GORE-TEX) grafts. RESULTS: Forty-seven consecutive new or established patients receiving chronic hemodialysis had grafts (25 ePTFE, 22 standard PTFE) placed between November 1994 and July 1995. There were no significant differences between the groups in age, race, gender, incidence of diabetes mellitus, or peripheral vascular disease. By the end of the study, 21 of 25 ePTFE grafts had clotted, compared with 11 of the 22 patients receiving a standard PTFE graft. Median time to first clotting was 53 days for the ePTFE grafts and 164 days for the standard PTFE grafts (p < 0.0001). Nine patients with ePTFE grafts required a temporary catheter after their first clotting episode. CONCLUSIONS: The ePTFE grafts thrombosed at a significantly higher rate than standard wall PTFE grafts. Further experience with the Diastat graft might improve graft survival. However, early experience does not suggest that the avoidance of short-term temporary access outweighs the problem of high clotting rate, and its attendant morbidity.

A pharmacoeconomic comparison of antithymocyte globulin and muromonab CD3 induction therapy in renal transplant recipients.

Antithymocyte globulin (ATG) and muromonab CD3 (OKT3) are currently the only antilymphocyte preparations that are commercially available for induction immunosuppressive therapy for renal allograft transplantation in the US. ATG, in the usually prescribed doses, is more expensive than muromonab CD3, but muromonab CD3 is associated with more severe adverse effects that may affect clinical outcome and overall cost. We performed a retrospective study of all adult recipients of a first cadaveric renal allograft, who underwent transplantation between January 1991 and December 1994 who received either ATG (n = 92) or muromonab CD3 (n = 91) for induction therapy at our transplant centre. The average age of recipients was older (50 vs 44 yrs; p = 0.001) and extended donors were more commonly used in the ATG group (41 vs 13%; p = 0.0001) compared with the muromonab CD3 group. Nevertheless, at 1 year post-transplant, the incidence of rejection was lower (34 vs 47%) and graft survival was better (93 vs 85%; p = 0.03) in the ATG group. Patients who received ATG were discharged earlier (9.4 vs 13.3 days; p = 0.0001) and had similar serum creatinine levels on the day of discharge (2.4 +/- 1.5 vs 2.1 +/- 1.1 mg/dl; p = 0.25). Overall, the 1-year hospitalisation costs of transplantation and readmissions were similar [$US39,937 +/- 17,014 vs $US42,850 +/- 20,923 (currency year 1994); p = 0.22]. This is the first comparison of ATG and muromonab CD3 in renal transplant recipients to consider clinical as well as economic outcomes. For renal transplant patients in whom induction therapy is used at our centre, the initial expense of ATG can be justified by improved graft survival, fewer rejection episodes, and shorter hospital stays, which are associated with similar overall transplantation costs.