M. Roy First

A Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial Comparing Early (7 Day) Corticosteroid Cessation Versus Long-Term, Low-Dose Corticosteroid Therapy

Objective:To compare outcomes with early corticosteroid withdrawal (CSWD) and chronic low dose corticosteroid therapy (CCS). Summary Background Data:Final, 5-year results from the first randomized, double-blind, placebo-controlled trial of early CSWD (at 7 days posttransplant) are presented. Methods:Adult recipients of deceased and living donor kidney transplants without delayed graft function were randomized to receive prednisone (5 mg/d after 6 months posttransplant) or CSWD. Blinding was maintained for 5 years. This clinical trial is registered at www.clinicaltrials.gov (NCT00650468). Results:Results in 386 patients CSWD (n = 191), CCS (n = 195) are presented (CSWD; CCS). No differences were observed at 5 years in the proportion of patients experiencing: primary end point (composite of death, graft loss, or moderate/severe acute rejection) (30/191 (15.7%); 28/195 (14.4%)), patient death (11/191(5.8%);13/195 (6.7%)), death-censored graft loss (11/191 (5.8%); 7/195(3.6%)), biopsy confirmed acute rejection (BCAR) (34/191 (17.8%); 21/195 (10.8%), P = 0.058), moderate/severe acute rejection (15/191 (7.9%); 12/195 (6.2%)). Kaplan Meier analyses of the primary end point and its components also showed no differences; but BCAR was higher with CSWD (P = 0.04). Increased BCAR episodes were primarily corticosteroid-sensitive Banff 1A rejections: the incidence of antibody-treated BCAR was similar between groups (11/191 (5.8%); 13/195 (6.7%)). No differences in renal function were observed at 5 years: mean serum creatinine (1.5 ± 0.6; 1.5 ± 0.7 mg/dL), or Cockroft Gault calculated creatinine clearance (58.6 ± 19.7; 59.8 ± 20.5 mL/min). CSWD was associated with improved serum triglycerides (evaluated by mean and median change from baseline) at all time points (except at 5 years measured by mean change). Weight change also demonstrated changes favoring CSWD (median change from baseline at 5 years: 5.1 vs. 7.7 kg, P = 0.05). New onset diabetes after transplant (NODAT) was similar with respect to proportions who required treatment (23/107 (21.5%)); 18/86 (20.9%); however, fewer CSWD patients required insulin for NODAT at 5 years (4/107 (3.7%)); 10/86 (11.6%), P = 0.049). Changes in HgA1c values (from baseline) were lower in CSWD patients at all time points except 4 years. Conclusions:Early CSWD, compared with CCS, is associated with an increase in BCAR primarily because of mild, Banff 1A, steroid-sensitive rejection, yet provides similar long-term renal allograft survival and function. CSWD provides improvements in cardiovascular risk factors (triglycerides, NODAT requiring insulin, weight gain). Tacrolimus/MMF/antibody induction therapy allows early CSWD with results comparable to long-term low dose (5 mg/d) prednisone therapy.

Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation

BACKGROUND Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Alemtuzumab induction in renal transplantation.

BACKGROUND There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

Recurrent and de novo glomerular disease after renal transplantation : A report from renal allograft disease registry (RADR)

INTRODUCTION Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.

One‐Year Results with Extended‐Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients

Once‐daily tacrolimus extended‐release formulation (Prograf XL, formerly referred to as MR or MR4) was compared with the twice‐a‐day tacrolimus formulation (TAC) and cyclosporine microemulsion (CsA), all administered in combination with mycophenolate mofetil (MMF), corticosteroids and basiliximab induction, in a phase 3, randomized (1:1:1), open‐label trial in 638 de novo kidney transplant recipients. In combination with MMF and corticosteroids, XL had an efficacy profile comparable to TAC and CsA. XL/MMF and TAC/MMF were statistically noninferior at 1‐year posttransplantation to CsA/MMF for the primary efficacy endpoint, efficacy failure (death, graft loss, biopsy‐confirmed acute rejection (BCAR) or lost to follow‐up). One‐year patient and graft survival were 98.6% and 96.7% in the XL/MMF group, 95.7% and 92.9% in TAC/MMF group and 97.6% and 95.7% in CsA/MMF group. The safety profile of XL in comparison with CsA was similar to that observed with TAC in this study and consistent with previously published reports of TAC in comparison with CsA. The results support the safety and efficacy of tacrolimus in combination with MMF, corticosteroids and basiliximab induction, as well as XL as a safe and effective once‐daily dosing alternative.

Posttransplant diabetes mellitus in kidney allograft recipients: Incidence, risk factors, and management

BACKGROUND Posttransplant diabetes mellitus (PTDM), associated with the use of immunosuppressants, occurs at varying rates in kidney transplant recipients. METHODS Five transplant centers conducted a retrospective review of 435 kidney recipients completing at least 6 months of follow-up to determine risk factors, incidence, and management strategies for posttransplant glucose intolerance. A distinction was made between hyperglycemia and diabetes. RESULTS The incidence of PTDM was found to be 4.9%. Among tacrolimus-treated patients it was 5.7%, compared with 3.3% among cyclosporine-treated patients (P=0.453). Mean daily maintenance doses of prednisone and mycophenolate mofetil (MMF) were significantly lower in tacrolimus-treated patients. Significantly more tacrolimus-treated patients were prednisone-free (9.0%/0%; P<0.001). Logistic regression analysis revealed that the absence of an antiproliferative agent correlated with the development of PTDM (odds ratio=3.56; P=0.01). CONCLUSIONS Based on this study, we propose management guidelines specifically for glucose intolerance developing after renal transplantation. Maintenance of blood glucose levels within strict limits is recommended, and the contribution of immunosuppressive agents to the development of PTDM is accounted for. Gradual tapering of prednisone and tacrolimus is proposed for patients who develop PTDM but also bear minimal risk of rejection. Tapering and eventual withdrawal of insulin should be attempted once blood glucose levels normalize. Switching to the alternative calcineurin inhibitor should only be considered as a late intervention. Tacrolimus therapy should be considered even in patients at high risk for diabetes, because the benefit of reduced acute rejection incidence and severity, as demonstrated in other studies, outweighs the risk of PTDM.

De Novo Cancers Arising in Organ Transplant Recipients are Associated With Adverse Outcomes Compared With the General Population

Background. Transplant recipients are at increased risk of malignancy; however, the influence of transplantation on cancer outcomes has not been rigorously defined. The purpose of this study was to examine the influence of transplantation on the outcomes of individual cancers. Methods. De novo nonsmall cell lung cancer, colon cancer, breast cancer, prostate cancer, bladder cancer, renal cell cancer (RCC), and malignant melanoma data in 635 adult (>18 years of age) transplant recipients (from the Israel Penn International Transplant Tumor Registry) were compared with data from 1,282,984 adults in the general population (from the Surveillance, Epidemiology, and End Results database). Results. Compared with the general population, transplant patients were more likely to have early stage (AJCC stage 0–II) RCC, but more advanced (AJCC stage >II) colon cancer, breast cancer, bladder cancer, and malignant melanoma. Compared with the general population, disease-specific survival was worse in the transplant population for colon cancer (all stages), nonsmall cell lung cancer (stage II), breast cancer (stage III), prostate cancer (stage II, III, and IV), bladder cancer (stage III), and RCC (stage IV). Multivariate analyses demonstrated transplantation to be a negative risk factor for survival for each cancer studied, and transplantation and cancer stage at diagnosis to be the most profound negative survival predictors. Conclusions. These analyses indicate that, for several common cancers, transplant patients experience worse outcomes than the general population. The data also suggest that cancers in transplant recipients are more aggressive biologically at the time of diagnosis.

PROTEINURIA FOLLOWING TRANSPLANTATION: Correlation With Histopathology And Outcome

A review of 693 renal transplant recipients revealed 77 (11%) in whom persistent, heavy proteinuria (>2 g/ 24 hr) developed. Renal histology was available in all 77 patients. Twenty-one patients had received kidneys from living-related donors, the remaining 56 from cadaveric donors. The cause of proteinuria in these 77 patients was as follows: transplant glomerulopathy (30), allograft glomerulonephritis (22), chronic rejection (21), renal vein thrombosis (2), diabetic glomerulosclerosis (1), and hypertensive nephrosclerosis (1). Of the 22 patients who developed glomerulonephritis in the transplanted kidney, 6 had recurrent disease (3—membranous glomerulopathy, 2—focal sclerosis and hyali- nosis, 1—membranoproliferative glomerulonephritis); 6 developed de novo glomerulonephritis; and in 10 the type of glomerulonephritis could not be classified as recurrent or as de novo because of lack of characterization of the original kidney disease. Renal vein thrombosis occurred in association with other lesions in an additional 5 cases (3—chronic rejection; 2—membranous glomerulopathy). In follow-up only 23.4% (18 of 77) of the patients maintained prolonged graft function; the majority of grafts being lost within one year of the development of persistent, heavy proteinuria. Of the 18

Donors with central nervous system malignancies: are they truly safe?

Background. In an era of organ shortage, the use of expanded or marginal donors has been attempted to increase transplantation rates and diminish waiting list mortality. One strategy is the use of organs from patients with a history of or active central nervous system (CNS) tumor. Methods. Sixty-two recipients were identified as the recipients of organs from donors with a history of or active CNS malignancy. Patient demographics, donor tumor management, incidence of tumor transmission, and patient survival were examined. Results. Of the organs recovered and transplanted from donors with astrocytoma, 14 were associated with at least one risk factor including high-grade tumor (n=4), prior surgery (n=5), radiation therapy (n=4), and systemic chemotherapy (n=4). One tumor transmission was identified at 20 months posttransplant with the patient expiring from metastatic disease. Twenty-six organs were transplanted from glioblastoma patients with 15 demonstrating risk factors including high-grade tumor (n=9) and prior surgery (n=10). Eight transmissions were identified with a range of 2 to 15 months posttransplant, with seven patients dying as the result of metastatic disease. Seven organs were used from donors with a medulloblastoma. Three transmissions were identified at a range of 5 to 7 months, all associated with ventriculoperitoneal shunts. Two medulloblastoma recipients died as the result of metastatic disease, whereas the third is alive with diffuse disease. The rate of donor tumor transmission, in the absence of risk factors, was 7%, whereas in the presence of one or more risk factor this rate dramatically rose to 53% (P <0.01). Conclusions. Organs from donors with CNS tumors can be used with a low risk of donor tumor transmission in the absence of the following risk factors: high-grade tumors, ventriculoperitoneal or ventriculoatrial shunts, prior craniotomy, and systemic chemotherapy.

Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients.

Background. In view of the superior T-cell depletion and prolonged half-life of thymoglobulin, we initiated a protocol to administer thymoglobulin intermittently based on peripheral blood CD3+ lymphocyte counts. Methods. In this prospective study, 41 consecutive high-risk cadaver transplant recipients (panel reactive antibody level >30%, repeat transplant recipients, simultaneous pancreas and kidney or pancreas after kidney recipients, prolonged cold-ischemia time, prolonged donor hypotension, non-heart-beating donors) who received thymoglobulin induction therapy were included. The first dose (1.5 mg/kg) of thymoglobulin was administered intraoperatively. CD3+ lymphocyte count in the peripheral blood was determined daily and repeat doses were administered when the CD3+ count was >20 cells/mm3. Calcineurin inhibitors (CI) in low doses were introduced when the allograft function recovered and the serum creatinine level dropped by at least 25% from the pretransplant level. Thymoglobulin treatment was discontinued once therapeutic CI drug levels were achieved. Concomitant immunosuppression consisted of mycophenolate mofetil and prednisone. Results. The mean individual thymoglobulin dose was 104 mg (1.4 mg/kg), and the total cumulative dose per patient was 318 mg (4.2 mg/kg). Patients received an average of three doses and a mean of six CD3 counts were obtained per patient. Introduction of CI was delayed for an average of 6 days posttransplantation. At a mean follow-up of 340 days, two (4.9%) patients died; three (7.3%) renal allografts and two (18.2%) pancreas allografts were lost. Five (12.2%) patients developed a total of six acute rejection episodes. The mean serum creatinine in the 38 patients with a functioning kidney was 1.47 mg/dl, and the mean blood glucose in the 9 pancreas allograft recipients was 89 mg/dl. Cytomegalovirus (CMV) infection occurred in one (2.4%) patient. No posttransplant lymphoproliferative disorders were seen in this patient cohort. The hospital pharmacy charge for a 100-mg dose of thymoglobulin at this center was