Search

Background: Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. Methods: 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. Findings: We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13-18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13-18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). Interpretation: The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2 ± 2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or Improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Purpose. The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed. Methods. From July 4, 1994 until April 30, 1998, 147 pancreas transplantations were performed in 141 patients, including 126 simultaneous pancreas-kidney transplantations, 13 pancreas after kidney transplantation, and 8 pancreas transplantations alone. Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Twenty-three patients were excluded from analysis because of early graft loss in 17 cases, retransplantation in 5 cases, and simultaneous pancreas-kidney transplantation after heart transplantation in 1 patient. Results. With a mean follow-up of 2.8±1.1 years (range 1.0 to 4.8 years), complete steroid withdrawal was achieved in 58 (47%) patients with a mean time to steroid withdrawal of 15.2±8 months (range 4 to 40 months after transplantation). Of the entire cohort of 141 patients, overall 1-, 2-, and 4-year patient survival rates were 98%, 95.5%, and 86%, respectively. Overall 1-, 2-, and 4- year graft survival rates were 83%, 80%, and 71% (pancreas) and 95%, 91%, and 84% (kidney), respectively. Of the 124 patients analyzed for steroid withdrawal, 1-, 2-, and 4-year patient survival rates were 98%, 97%, and 92%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 98%, 91.5%, 83% (pancreas) and 97%, 95%, and 91% (kidney). Patient, pancreas, and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids) versus 97%, 91%, and 96% (on steroids, all NS) and at 4 years were 100%, 94%, and 95% (off steroids) versus 78%, 68%, and 85% (on steroids, P=0.01, 0.002, and NS, respectively). The cumulative risk of rejection at the time of follow-up was 76% for patients on steroids versus 74% for patients off steroids (P=NS). Seven patients originally tapered off steroids were treated for subsequent rejection episodes, which were all steroid sensitive, and two of these seven patients

Background. Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression. Methods. Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF → ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59±23 months. Results. The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF → ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF → ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF → ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn fr

Objective: The effect of donor bone marrow was evaluated for its potentially favorable effect in the authors' simultaneous pancreas/kidney transplant program. Methods: From July 1994 to January 1999, 177 pancreas transplants were performed, 151 of which were simultaneous pancreas/kidney transplants. All patients received tacrolimus, mycophenolate mofetil, and steroids for immunosuppression (azathioprine was used in the first year of the program). Fifty-three simultaneous pancreas/kidney transplant recipients received perioperative unmodified donor bone marrow, 3 to 6 x 108 cells/kg. Results: Overall actuarial survival rates at 1 and 3 years were 98% and 95% (patient), 95% and 87% (kidney), and 86% and 80% (pancreas), respectively. In the adjuvant bone marrow group, 1- and 3-year survival rates were 96% and 91% (patient), 95% and 87% (kidney), and 83% and 83% (pancreas), respectively. For 98 recipients who did not receive bone marrow, survival rates at 1 and 3 years were 100% and 98% (patient), 96% and 86% (kidney), and 87% and 79% (pancreas), respectively. No pancreas allografts were lost after 3 months in bone marrow recipients, and seven in the non-bone marrow recipients were lost to rejection at 0.7, 6.7, 8.8, 14.6, 24.1, 24.3, and 25.5 months. Twenty-two percent of bone marrow patients were steroid-free at 1 year, 45% at 2 years, and 67% at 3 years. Nineteen percent of the non-bone marrow recipients were steroid-free at 1 year, 38% at 2 years, and 45% (p = 0.02) at 3 years. The mean acute cellular rejection rate was 0.94 ± 1.1 in the bone marrow group and 1.57 ± 1.3 (p = 0.003) in the non-bone marrow group (includes borderline rejection and multiple rejections). The level of donor cell chimerism in the peripheral blood of bone marrow patients was at least two logs higher than in controls. Conclusion: In this series, which represents the largest experience with adjuvant bone marrow infusion in pancreas recipients, there was a higher steroid withdrawal rate (p = 0

Background. Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6±5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3±14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5±8.8 hr. The mean number of HLA matches and mismatches was 2.8±1.2 and 2.9±1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0±0.2 years. Results. The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1±0.5 mg/all, and the corresponding calculated creatinine clearance was 88±25 ml/min/1.73 m2. A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were - 2.3±2.0, -1.7±1.0, and +0.36±1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. Th

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P<.0001). PTLD was diagnosed 21.0±22.5 months after transplantation, 25.0±24.7 months in adults and 14.4±18.2 months in pediatric patients. Of the 4 adult cases in whom both the donor and recipient Epstein Barr virus (EBV) serologies were known, 2 (50%) were seropositive donor → seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor → seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9 ±30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5±1.2 mg/dl, and in children, it was 1.3±0.6 mg/dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in chil

Background. The long-term safety and efficacy of tacrolimus in pancreas transplantation has not yet been demonstrated. The observation of prolonged pancreatic graft function under tacrolimus would indicate that any potential islet toxicity is short-lived and clinically insignificant. We report herein the results of pancreas transplantation in patients receiving primary tacrolimus immunosuppression for a minimum of 2 years. Methods. From July 4, 1994 until April 18, 1996, 60 patients received either simultaneous pancreas- kidney transplant (n=55), pancreas transplant only (n=4), or pancreas after kidney transplantation (n=1). Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Azathioprine was used as a third agent in 51 patients and mycophenolate mofetil in 9. Rejection episodes within the first 6 months occurred in 48 (80%) patients and were treated with high-dose corticosteroids. Antilymphocyte antibody was required in eight (13%) patients with steroid-resistant rejection. Results. With a mean follow-up of 35.1±5.9 months (range: 24.3-45.7 months), 6-month and 1-, 2-, and 33-year graft survival is 88%, 82%, 80%, and 80% pancreas) and 98%, 96%, 93%, and 91% (kidney), respectively. Six-month and 1-, 2-, and 3-year patient survival is 100%, 98%, 98%, and 96.5%. Mean fasting glucose is 91.6±13.8 mg/dl, and mean glycosylated hemoglobin is 5.1±0.7% (normal range: 4.3-6.1%). Mean tacrolimus dose is 6.5±2.6 mg/day and mean prednisone dose 2.0±2.9 mg/day at follow-up. Complete steroid withdrawal was possible in 31 (65%) of the 48 patients with functioning pancreases. Conclusions. These data show for the first time that tacrolimus is a safe and effective long-term primary agent in pancreas transplantation and provides excellent long-term islet function without evidence of toxicity while permitting steroid withdrawal in the majority of patients.

Background. Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. Methods. The mean recipient age was 50.7±13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5±21.7 years. The mean cold ischemia time was 30.5±9.2 hr. The mean follow-up is 15±7 months. Results. The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6±0.8 mg/dL A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. Conclusions. This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

Advances in the surgical techniques, preservation solutions, and methods for predicting eventual long-term renal function from expanded donors will be critical in allowing precise selection criteria for kidneys for transplantation, resulting in the optimum use of a scarce and precious resource. Until other options such as xenotransplantation or tissue engineering become realistic, the challenge for the millennium will be to identify which donor organs previously considered suboptimal can be safely used to expand the organ donor pool. © 1999 by Elsevier Science Inc.

PURPOSE: Between September 20, 1995 and September 20, 1996, 120 patients were entered into a prospective, randomized trial comparing tacrolimus and prednisone with (61) and without (59) 2 gm. mycophenolate mofetil daily to determine whether mycophenolate mofetil was associated with a lower incidence of rejection. MATERIALS AND METHODS: Mean recipient age plus or minus standard deviation was 50.8+/-14.1 years (range 18.8 to 84.1). Mean donor age was 34.3+/-21.7 years (range 0.01 to 76). Of the donors 18 (15%) were older than 60 years. Mean cold ischemia time was 30.9+/-8.4 hours (range 14.2 to 49). Median followup was 8.6+/-0.5 months. RESULTS: The 6-month actuarial patient survival was 95%, 92% in the double therapy group and 98% in the triple therapy group (not significant). The 6-month actuarial graft survival was 88%, 84% in the double therapy group and 92% in the triple therapy group (not significant). The overall incidence of rejection and steroid resistant rejection was 34.2 and 4.2%, respectively. There was a strong trend toward less rejection in the mycophenolate mofetil group than in the double therapy group (26.2 versus 42.4%). Crossover was common, and was 42.6% from triple to double therapy and 18.6% from double to triple therapy. The reasons for discontinuation of mycophenolate mofetil were gastrointestinal toxicity, primarily diarrhea, or less commonly hematological toxicity, primarily neutropenia or thrombocytopenia. Gastrointestinal toxicity was ameliorated by separating the doses of tacrolimus and mycophenolate mofetil by 2 to 4 hours, and reducing the dose to 1 gm. daily. CONCLUSIONS: Mycophenolate mofetil appears to be a useful third agent with tacrolimus in patients undergoing renal transplantation, and is associated with a reduction in the rate of rejection and a low incidence of steroid resistant rejection. There is a high incidence of gastrointestinal toxicity associated with the 2 gm. daily dose but this complication is relatively straightfor

Over the 5 year period from 7/14/1989 until 5/24/1994, we have attempted graft salvage with tacrolimus conversion in a total of 169 patients (median age 33 years, range 2-75 years) with ongoing rejection on baseline CsA immunosuppression after failure of high dose corticosteroids and/or antilymphocyte preparations to reverse rejection. The indications for conversion to tacrolimus were ongoing, biopsy confirmed rejection in all patients. The median interval to tacrolimus conversion was 2 months (range 2 days to 55 months; mean 4.3±2.6 months) after transplantation. All patients had failed high dose corticosteroid therapy and 144 (85%) of the 169 patients had received at least one course of an antilymphocyte preparation plus high dose corticosteroid therapy prior to conversion. Twenty-eight patients (17%) were dialysis-dependent at the time of conversion owing to the severity of rejection. With a mean follow-up of 30.0±2.4 months (median 36.5 months, range 12-62 months), 125 of 169 patients (74%) have been successfully rescued and still have functioning grafts with a mean serum creatinine (SCR) of 2.3±1.1 mg/dl. Of the 144 patients previously treated with antilymphocyte preparations, 117 (81%) were salvaged. Of the 28 patients on dialysis at the time of conversion to tacrolimus, 13 (46%) continue to have functioning grafts (mean SCR 2.15±0.37 mg/dl) at a mean follow-up of 37.3±16.7 months. In the 125 patients salvaged, prednisone doses have been lowered from 28.0±9.0 mg/d (median 32, range 4-60 mg/d) preconversion to 8.5±4.1 mg/d (median 12 mg/d, range 2.5-20 mg/d) postconversion. Twenty-eight patients (22.4%) are currently receiving no steroids. This 5 year experience demonstrates that tacrolimus has sustained efficacy as a rescue agent for ongoing renal allograft rejection. Based on these data, we recommend that tacrolimus be used as an alternative to the conventional drugs used for antirejection therapy in renal transplantation.

Female, pediatric, and older donors have been associated with inferior graft survival after renal transplantation. We analyzed these three subgroups in 397 patients receiving tacrolimus-based immunosuppression. There were no differences in recipient age, incidence of retransplantation, or percentage of sensitized patients. Female donors, compared with male donors, were associated with comparable 1- and 3-year patient survival rates (96% and 93% vs. 95% and 92%, respectively) and comparable 1- and 3-year graft survival rates (90% and 80% vs. 88% and 81%, respectively). Renal function was also similar. Recipients of pediatric en bloc kidneys, when compared with recipients of other cadaveric kidneys, also had comparable 1- and 3-year patient survival rates (94% and 94% vs. 95% and 91%, respectively) and comparable 1- and 3-year graft survival rates (84% and 84% vs. 89% and 79%, respectively). Renal function was better in recipients of en bloc kidneys, with a mean serum creatinine level of 1.4±1.8 mg/dl vs. 2.0±1.5 mg/dl (P=0.01). In contrast to the first two subgroups, donors over 60 years of age, when compared with donors under 60 years of age, were associated with worse 1- and 3-year patient survival rates (88% and 80% vs. 96% and 94%, respectively; P<0.03) and worse 1- and 3-year graft survival rates (74% and 62% vs. 91% and 83%, respectively; P<0.0001). Renal function was worse in the older donor group, with a serum creatinine level of 2.7±1.2 mg/ml vs. 1.9±1.5 mg/dl (P=0.01). We conclude that, under tacrolimus-based immunosuppression, kidneys from female or very young pediatric donors are not associated with adverse outcomes, whereas kidneys from donors over 60 years of age are associated with inferior outcomes.

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3±5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0±14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0±9.4 hr. The antigen match was 2.7±1.2, and the mismatch was 3.1±1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32±20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2±0.8 mg/dl, and the calculated creatinine clearance was 82±26 ml/min/1.73 m2. The mean tacrolimus dose was 0.22±0.14 mg/kg/day, and the level was 9.5±4.8 ng/ml. The mean prednisone dose was 2.1±4.9 mg/day (0.07±0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158±54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lym

On the basis of observations in patients with longterm (28-30 years) renal allograft survival, all of whom had evidence of systemic microchimerism, we began a program of combined simultaneous kidney/bone marrow transplantation. Between 12/14/92, and 10/31/94,36 kidney transplant recipients received 3-5 x 108 unmodified bone marrow cells/kg; 6 patients also received pancreatic islets, and 7 patients also received a pancreas. The mean recipient age was 39.0 ±10.8 years, and the mean donor age was 31.8 ±16.1 years; the mean cold ischemia time was 23.0±9.1 hr. Twenty control patients received kidneys alone, mainly because of refusal by the donor family to consent to vertebral body recovery; 3 of these patients also received a pancreas. The mean recipient age was 47.9 ±11.7 years, and the mean donor age was 41.5 ±17.9 years; the mean cold ischemia time was 28.6 ±6.2 hr. All patients received tacrolimus-based therapy, without radiation, cytoreduction, or induction antilymphocyte preparations. Blood was drawn prior to and at regular intervals after transplantation for detection of chimerism and for immunologic studies. With a mean follow-up of 11.1 ±5.8 months, all 36 study patients are alive, and 33 (92%) have functioning allografts with a mean serum creatinine of 1.9±1.2 mg/dl and a BUN of 26±9 mg/dl. Graft vs. host disease was not seen in any patient. The incidence of rejection was 72%; 11% of the patients required OKT3 or ATG for steroid-resistant rejection. The incidence of CMV was 14%, and that of delayed graft function was 17%. A total of 18 (90%) control patients are alive, and 17 (85%) have functioning allografts, with a mean serum creatinine of 2.1 ±1.3 mg/ dl, and a BUN of 30±13 mg/dl. The incidence of rejection was 60%, and 10% required OKT3 or ATG. CMV was seen in 15%, and delayed graft function in 20% (P=NS). In the study patients, chimerism was detected in the peripheral blood of 30 of 31 (97%) evaluable patients by either PCR or flow cytometry. In the contr

A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/pred-nisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11,1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel-reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8±13.7 years (range 17.6-78). The mean donor age was 34.0±20.1 years (range 0.3-75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4±8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow-up was 22±4 months (range 12-29). Overall one-year actual patient survival was 94%. Overall one-year actual graft survival was 87%. Patients starting on double therapy had a one-year actual patient survival of 96% and a one-year actual graft survival of 92%. Patients starting on triple therapy had a one-year actual patient survival of 91% (P=ns compared with double therapy), and a one-year actual graft survival of 82% (P<0.02, compared with double therapy). Overall results with first cadaver transplants included a one-year actual patient survival of 94% and one-year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P<.07). The incidence of steroid-resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8±0.8 mg/dl. The mean BUN was 33±21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was

Tacrolimus is a superior immunosuppressive agent in patients undergoing renal transplantation. In adults, the 1- and 3-year actuarial patient survivals were 95% and 92%, and the 1- and 3-year actuarial graft survivals were 89% and 80%. For first cadaver kidneys, the 1- and 3-year actuarial graft survivals were 91% and 82%, with a projected half-life of 11.9 years. Sixty-nine percent of successfully transplanted patients were weaned off steroids. In pediatric patients, the 1- and 4-year actuarial patient survivals were 100% and 96%, and the 1- and 4-year actuarial graft survivals were 99% and 85%. Seventy-three percent of successfully transplanted children were weaned off steroids. Tacrolimus was also useful as a rescue agent, with an initial success rate of 74%. Tacrolimus has been used successfully in kidney/ pancreas transplantation, with 100% patient, 95% kidney, and 79% pancreas graft survival. Tacrolimus should be considered the immunosuppressive agent of choice in renal transplantation.

Seventy-seven patients with ongoing acute rejection on initial CsA therapy were converted to FK506 to attempt graft salvage. Fifty-nine patients had undergone primary transplantation and 18 had been retransplanted; there were 52 cadaveric and 25 living-donor transplants. The indications for conversion to FK506 were ongoing, biopsy-confirmed rejection in all patients, including vascular rejection in 20. The median interval to rescue was 2 months (range 2 weeks to 36 months) after transplantation. Sixty-one of the 77 patients (79%) had already received one or more courses of an antilymphocyte preparation (OKT3: n=33; ALG or ATG: n=1; OKT3+ALG/ATG: n=27). Of the 77 patients, 57 (74%) have been successfully rescued and still have functioning grafts with a mean follow-up of 14 months, with a mean serum creatinine of 2.35±0.97 mg/dl. Eighteen patients were already dialysis-dependent at the time of conversion to FK506; of these, 9 (50%) were successfully salvaged and have a mean serum creatinine of 2.3 mg/dl. Of the 61 patients previously treated with antilymphocyte preparations, 48 (79%) were rescued. In those salvaged, prednisone doses have been lowered from 22.2±7.2 mg/day preconversion to 7.5±5.6 mg/day postconversion, and 12 patients are on FK506 monotherapy. In nondiabetics, mean serum glucose was 101.4±20.5 mg/dl preconversion and 93.2±22 postconversion (P=0.07), uric acid 7.3±2.3 and 7.1±1.5 mg/dl (P=0.53), and triglycerides 199.2±101.6 and 167.2±106.4 mg/dl (P=0.06). Cholesterol levels were significantly lower following FK conversion (207.7±46.5 mg/dl pre. vs. 188.3±39.7 post, P=0.007). FK506 is capable of salvaging renal allografts with ongoing acute rejection on CsA therapy, even when antilymphocyte preparations have been ineffective. © 1994 by Williams and Wilkins.

1. In an unselected adult renal transplant population, FK506 as the primary immunosuppressive agent yielded one- and 2-year actuarial patient survival rates of 95% and 93% and one- and 2-year actuarial graft survival rates of 89% and 83%, respectively. Forty-nine percent of successfully transplanted patients were weaned off steroids. 2. In pediatric renal transplant patients, FK506 has been associated with 100% one- and 3-year actuarial patient survival rates and 98% and 85% one- and 3-year actuarial graft survival rates, respectively. Sixty-two percent of successfully transplanted patients were taken off prednisone, with dramatic improvements in height. 3. FK506 has been used successfully in rescuing 70-74% of adult or pediatric renal transplant patients with an acute rejection that failed conventional therapy. 4. Kidney/bone marrow transplantation under FK506 therapy has been successfully performed without graft-versus-host disease and with routine augmentation of chimerism. 5. The side effects of FK506 included nephrotoxicity, neurotoxicity, and diabetogenicity; they were comparable to those seen with CsA. 6. FK506 is an important new addition to the immunosuppressive armamentarium in renal transplant patients.

FK 506 was used as a primary immunosuppressive agent in 125 cases of renal transplantation in a randomized trial comparing FK 506/prednisone with FK 506/azathioprine/prednisone. With a mean follow-up of 5.5 +/- 2.5 months, there has been a 6-month actuarial patient survival of 99% and graft survival of 88%. There is no difference thus far between the two-drug and three-drug groups, although there may be less rejection and diabetes in the three-drug group. These results suggest that FK 506 is a useful immunosuppressive agent in kidney transplantation.

Extensive hepatocellular adenomatosis (HA) and focal nodular hyperplasia (FNH) represent a proliferation of hepatic cells that occurs most frequently in women. These lesions are uncommon in the pediatric age group, accounting for 2% of pediatric hepatic tumors, and are extremely rare in males. The etiology of HA and FNH has been correlated with the use of oral contraceptives. We report to the best of our knowledge the first series of patients treated with OLTx for HA and FNH (five cases). All these patients had lesions involving at least 90% of the hepatic parenchyma and all underwent major hepatic surgery before OLTx because of life threatening complications. One patient died in the immediate postoperative period following retransplantation for primary non-function of the first OLTx. Four out of five patients are currently alive from 4.1 to 9.6 years after OLTx. Our results justify the use of OLTx for symptomatic patients with HA and FNH who cannot be treated with conventional hepatic resections.

Seventy-four consecutive pediatric liver transplant recipients were reviewed to assess the effect of the monoclonal anti-T-lymphocyte antibody OKT3 on subsequent viral infection (9 patients were excluded due to postoperative demise during the 1st week). Twenty-two patients received OKT3 in addition to standard cyclosporine-prednisone immunosuppression for either steroid-resistant acute rejection (18) or to facilitate reduction of cyclosporine due to severe renal impairment (4). Invasive infections were diagnosed by histology or culture in tissue biopsies or bronchoalveolar lavage specimens. The overall incidence of viral infection was 58%, half of which was due to cytomegalovirus (CMV). Invasive viral disease was associated with increased mortality (37% vs. 3% p = 0.001). Viral-related deaths were due to CMV (5), disseminated adenovirus (3), disseminated enterovirus (1) and respiratory syncytial viral pneumonia (1). The use of OKT3 was associated with increased viral disease (59% vs. 33% p = 0.04) and invasive primary CMV disease (58% vs. 19% p = 0.04). Trends were observed toward increased overall viral infection (73% vs. 51% p = 0.08), primary CMV infection (58% vs. 25% p = 0.08) and overall mortality (27% vs. 9% p = 0.08) following OKT3 therapy. We conclude that pediatric liver transplant recipients who require OKT3 therapy may be at increased risk for invasive viral disease and especially invasive primary CMV disease.

A 17‐yr‐oId female received a liver transplant for type I glycogen storage disease. A year later, when she experienced variceal gastrointestinal hemorrhage, an angiogram revealed thrombosis of the portal vein with hepatopetal collateral channels. A distal splenorenal shunt was performed because of failure of sclerotherapy to control subsequent bleeding episodes and the fact that the liver function was normal. This patient continues to have normal hepatic function with a patent splenorenal shunt 4 yr after the shunting procedure. This case illustrates the feasibility of a distal splenorenal shunt to alleviate portal hypertension in cases of thrombosis of the portal vein following hepatic transplantation if the liver function is normal. Copyright © 1989, Wiley Blackwell. All rights reserved

Stenosis of the portal vein anastomosis occurred in three pediatric patients seven to 42 months after transplantation. Dominant symptoms were those of portal hypertension and hypersplenism. Diagnosis was made by angiography. Successful surgical reconstruction was possible in all three patients. © 1989, American Medical Association. All rights reserved.