C Vivas

A PROSPECTIVE, RANDOMIZED TRIAL OF TACROLIMUS/PREDNISONE VERSUS TACROLIMUS/PREDNISONE/MYCOPHENOLATE MOFETIL IN RENAL TRANSPLANT RECIPIENTS

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.

Tacrolimus rescue therapy for renal allograft rejection - Five-year experience

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.

TACROLIMUS IN PEDIATRIC RENAL TRANSPLANTATION

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 lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.

Suboptimal kidney donors: The experience with tacrolimus-based immunosuppression

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.

Renal allograft rejection with normal renal function in simultaneous kidney/pancreas recipients: does dissynchronous rejection really exist?

BACKGROUND Between July 1, 1994 and December 1, 1998, 147 simultaneous kidney/pancreas transplantations were performed at our center. Of 95 patients who experienced at least one acute renal allograft rejection episode after transplantation, 7 (7.4%) developed rejection in the presence of stable and normal or near-normal renal function. METHODS The indication for renal allograft biopsy was a rising serum lipase, i.e., suspected pancreatic rejection. All seven patients were treated with steroids and augmentation of the tacrolimus dose, with a fall in the serum lipase and no change in the serum creatinine. RESULTS The serum creatinine levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1.4+/-0.4, 1.3+/-0.3, 1.2+/-0.2, and 1.2+/-0.2 mg/dl. The serum lipase levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1022+/-1157 mg/dl, 874+/-996 mg/dl, 243+/-260 mg/dl, and 94+/-75 mg/dl. The tacrolimus dosages and levels at the time of the biopsy and 1 week later were 14.9+/-5.0 mg/day and 15.0+/-4.0 ng/ml, and 16.4+/-6.3 mg/day and 15.1+/-6.8 ng/ml. CONCLUSIONS These findings suggest that, in patients undergoing simultaneous kidney/pancreas transplantation, the entity of dissynchronous pancreatic allograft rejection without renal allograft rejection may not really exist. These data also make an additional fundamental point that acute rejection may occur in patients with normal and stable renal function.

Outcome After Steroid Withdrawal in Renal Transplant Patients Receiving Tacrolimus-Based Immunosuppression

Among the advantages of tacrolimus (Prograf FK506)-based immunosuppression in renal transplant patients has been the ability to withdraw steroids completely in the majority of successfully transplanted recipients. 1–4 The percentage of patients in whom steroids have been discontinued has varied with the length of follow-up, but has been as high as 70% or more.2,3 An important question, however, concerns the outcome in these patients, and to date, this issue has not been formally investigated. We looked at a large population of wellstudied patients entered into a prospective, randomized trial of two tacrolimus-based regimens, with and without azathioprine, to answer questions about the short- and medium-term safety of steroid withdrawal.

Reversibility of Tacrolimus-Induced Posttransplant Diabetes: An Illustrative Case and Review of the Literature

Tacrolimus is a potent immunosuppressive agent. It has been reported to have superior immunosuppressive efficacy when compared with the standard formulation of cyclosporine (CyA),1 based on its ability to rescue patients with failing allografts under CyA-based therapy,2,3 lower rejection rates when used as a primary immunosuppressive agent,4,5 and longer projected half-life.6 However, there have been reports of an increased incidence of posttransplant diabetes (PTDM) under tacrolimus-based therapy.4,5 We have reported on the reversibility of tacrolimus-induced PTDM in our own renal transplant patients.7,8 In this article, we present an illustrative case demonstrating the reversibility of PTDM and review both the published and unpublished literature. The data suggest that the initial incidence of PTDM in the renal transplant population may be higher under tacrolimus than under CyA-based therapy, but the final incidence is comparable.9–11

High risk donors - expanding donor criteria

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.

Tacrolimus without antilymphocyte induction therapy prevents pancreas loss from rejection in 123 consecutive patients

In this series, antilymphoid induction therapy did not appear to be necessary to prevent early graft loss from rejection. In addition, we have followed cytomegalovirus (CMV) antigenemia (pp65) for CMV infection. Although some patients developed a positive antigenemia in the seropositive to negative donor-recipient combinations, only one patient had a prolonged febrile course for 1 week.

Pancreas transplantation without antibody therapy

After whole organ pancreas transplantation with duodenojejunostomy to drain the exocrine secretions was reintroduced in 1984,1 a few centers adopted this technique to replace transplantation of the body and tail of the pancreas, which had been the procedure of choice in the 1970s and early 1980s. Although in the early clinical trials using cyclosporine in whole organ pancreas transplantation, the incidence of thrombosis appeared to be less than with transplantation of the tail or “pancreatic segment,” it was by no means insignificant, and it was considered that cyclosporine, given its vasoconstrictive properties, might be a contributing factor.2 However, there were other reasons why the pancreas was more prone to thrombosis than either the kidney or the liver, in both of which there is a much higher blood flow by comparison with the pancreas. These factors include twisting or compression of the portal vein, ischemic injury, pancreatitis, and reperfusion injury. In addition, acute rejection played a role in early pancreas allograft loss. Therefore, it was believed that if a lower dose of cyclosporine (or no cyclosporine at all) was used in combination with an anti-T cell antibody administered during the first 10 days following transplantation, the incidence of acute rejection and thrombosis would be reduced. Most pancreas transplant centers in the United States and Europe adopted this immunosuppression regimen with delayed introduction of cyclosporine, the so-called “quadruple sequential immunosuppressive therapy,” introduced by Sollinger.3 In the late 1980s and 1990s, both patient and graft survival improved with this regimen, probably more as a result of technical refinements and a more restrictive policy of donor and recipient selection, than improvement in immunosuppression. In spite of these better results, surgically-related morbidity remained high,4 but this phenomenon was not related to the choice of immunosuppressive regimen. By mid-1995, experience had been gained in a few centers using tacrolimus-based immunosuppression in pancreas transplantation, and a multicenter analysis was presented in a preliminary fashion in 1996 by Gruessner,5 and again, with more complete data and greater patient accrual in 1997 at the annual meeting of the American Society of Transplant Surgeons (ASTS).6 All of the contributing centers but one (Pittsburgh) used tacrolimus in combination with antibody induction. Results of the retrospective multicenter analysis. presented by Gruessner, showed a 1 year patient and graft survival of 97% and 85%, respectively.6 Although the Pittsburgh group, which did not use anti T-cell induction therapy, contributed more patients than each of the other centers, except the University of Minnesota, in the multicenter retrospective analysis, the majority of the patients in the study had received antibody induction. Graft success rates were better with tacrolimus-based immunosuppression than with other drug regimens. In addition, graft survival improved substantially with tacrolimus in patients receiving a pancreas without a kidney, ie, pancreas after kidney transplantation (PAK) and pancreas transplant alone (PTA).6,7 However, these “solitary” graft recipients also received anti T-cell induction therapy in addition to tacrolimus. Although the data clearly showed that tacrolimus was superior to cyclosporine, it was difficult to conclude in a definitive fashion that the addition of an anti-T-cell preparation in combination with tacrolimus was necessary.