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BACKGROUND In searching for an optimal induction regimen, we conducted two separate randomized trials of 38 living donor and 90 deceased donor adult, primary kidney transplant recipients comparing antithymocyte globulin (Thymoglobulin) (group A, N=43) versus alemtuzumab (group B, N=43) versus daclizumab (group C, N=42), using exactly the same three treatment arms in each trial. METHODS For the purpose of maximizing statistical power, results from the two randomized trials were combined. Groups A and C received standard maintenance dosing with tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids. Because of intense lymphodepletion expected with alemtuzumab use (and hoped-for achievement of a truer immunoregulatory state), group B received lower TAC and MMF dosing and corticosteroid avoidance. Long-term target TAC trough level and MMF dosing were 5 to 7 ng/mL and 1,000 mg b.i.d. in groups A and C; 4 to 6 ng/mL and 500 mg b.i.d. in group B. RESULTS With median follow-up of 95 months, biopsy-proven cute rejection incidence was similar in the three groups (8/43, 14/43, and 12/42, P=0.34), but biopsy-proven chronic allograft injury incidence was significantly higher in group B (19/43) in comparison with groups A (9/43) and C (7/42) combined (P=0.0008). Mean calculated creatinine clearance was significantly lower in group B versus the average of groups A and C means throughout 60 months posttransplant (62.9±4.2 vs. 83.6±6.9 and 79.8±5.9 at 60 months, P=0.01), and death-censored graft failure was significantly higher in group B (13/43) versus groups A (5/43) and C (5/42) combined (P=0.009). Total infection and new-onset diabetes after transplant rates were not significantly different. Ad hoc analysis suggested that the inferior results in group B were specifically a result of reduced dosing and greater withholding of TAC and MMF occurring in that group. CONCLUSIONS Long-term results clearly indicate inferior clinical outcomes in group B.

BACKGROUND In adult kidney transplantation, there is no clear consensus on the incidence of graft failure-due-to noncompliance (GFNC), with some reporting it as relatively uncommon and others as a major cause of late graft failure. We suspected that GFNC was a major cause of late graft loss at our center but did not know the extent of this problem. METHODS In our prospectively followed cohort of 628 adult, primary kidney-alone transplant recipients with long-term follow-up, GFNC and other graft loss causes were determined from our ongoing clinical evaluations. Using competing risks methodology, we determined the overall percentage of patients developing GFNC and the significant prognostic factors for its hazard rate and cumulative incidence (via Cox regression). RESULTS Cumulative incidence estimates (± standard error) of GFNC (n=29), GF-with-compliance (n=46), receiving a never-functioning graft (n=7), and death-with-a-functioning-graft (n=53) at 101 months after transplant (last-observed-graft loss) were as follows: 9.8%± 2.4%, 10.9%± 1.7%, 1.1%± 0.4%, and 13.0%± 1.9%, respectively. Only three patients experienced GFNC during the first 24 months; GFNC represented 48.1% (26/54) of death-censored GFs beyond 24 months. Two baseline variables were jointly associated with a significantly higher GFNC hazard and cumulative incidence: younger recipient age (P

BACKGROUND Transplant tolerance would remove the need for maintenance immunosuppression while improving survival and quality of life. METHODS A prospective, randomized pilot study was undertaken to assess the safety and efficacy of donor stem cell infusion (DSCI) in living-related kidney transplant recipients treated with alemtuzumab (C1H) induction and tacrolimus and mycophenolate maintenance with switch to sirolimus and weaning over 2 years. RESULTS Four patients received DSCI; five patients were controls. Graft failure occurred in two patients in the DSCI arm. Recurrence of glomerular disease occurred in two DSCI recipients, leading to graft loss in one. Biopsy-proven acute rejection episodes occurred in three patients (two in the DSCI vs. one in the control). One DSCI patient, with recurrence, subsequently developed antibody-mediated rejection leading to graft failure. In the remaining two DSCI patients, weaning was attempted but was not successful. All (4 of 4) DSCI patients had biopsy-proven chronic allograft injury and/or recurrence. CONCLUSION DSCI with C1H induction and a steroid-free maintenance regimen in a small group of patients failed to induce tolerance, with suboptimal patient and graft survival. The results do not justify extension of this particular trial and underscore the importance of patient selection, specifically avoidance of patients with glomerulopathies whose recurrence may obscure potential benefit.

Focal segmental glomerulosclerosis (FSGS) is a relatively prevalent glomerular disorder that often progresses to end-stage renal disease. Thirty to 80% of kidney transplant (KT) recipients with FSGS will experience recurrence characterized by proteinuria and podocyte damage. We hypothesized that the degree of podocyte foot process (FP) effacement in postreperfusion transplant biopsies can be used to predict the development of clinical recurrence of FSGS.Nineteen pairs of pre- and postreperfusion biopsy specimens were studied. We evaluated the degree of FP effacement in postreperfusion KT biopsies by counting the number of widened FP per capillary loop. Early recurrence of FSGS was defined as development of nephrotic range proteinuria between days 3 and 30 posttransplant.Early recurrence occurred in 7 of 19 grafts (36.8%) at a mean of 4.29±1.89 days. The mean score of FP effacement in postreperfusion allograft biopsies was 0.72±0.31 and 1.35±0.63 in the nonrecurrent and recurrent group, respectively (P=0.039). There was an association between FP effacement and proteinuria (P = 0.04). The FP effacement score predicts early recurrence with a sensitivity of 71.4% and specificity of 91.7%.FP effacement can be observed within minutes after reperfusion in renal transplantation of recipients with FSGS that will ultimately develop recurrent FSGS. This suggests a key role for the podocyte injury in the pathogenesis of recurrent FSGS and further supports the presence of circulating factors causing FP effacement. The FP effacement score in the postreperfusion KT biopsy may become a useful predictive test if validated in larger studies.

Background. Our single-center, open-labeled randomized trial of 150 adult, primary kidney transplant recipients receiving 2 g mycophenolate mofetil (group A, n = 75) versus 1.440 g enteric-coated mycophenolate sodium (group B, n=75), with reduced maintenance tacrolimus dosing, steroid elimination at 1 week, and combined rabbit antithymocyte globulin/daclizumab induction, previously showed at 1 year posttransplant low biopsy-proven acute rejection (BPAR), acceptably high renal function, and no differences in incidence of symptomatic gastrointestinal (GI) side effects between the two groups. This report includes 3 additional years of follow-up with similar endpoints as in the original study. Methods. Rates of developing first BPAR, graft failure (death censored and uncensored), death, and adverse events (GI toxicity, infections requiring hospitalization, and new onset diabetes mellitus after transplantation) during the first 48 months posttransplant were compared between the two groups using an intent-to-treat approach. Results. At 48 months posttransplant, patient/graft survival in groups A and B was 97%/90% vs. 96%/86%, respectively (not significant [NS]). Twenty-seven patients experienced BPAR (including borderline), with actuarial 19% (14/75) vs. 18% (13/75) in groups A and B, respectively (NS). Geometric mean * /standard error serum creatinine level and arithmetic mean calculated glomerular filtration rate (±standard error) at 48 months in groups A and B, respectively, were 1.25*/1.06 and 69.2 ±3.9 vs. 1.20*/1.05 and 71.2±3.2 (NS). Incidence of new onset diabetes mellitus after transplantation (22% vs. 15%), infections requiring hospitalization (31% vs. 39%), and GI side effects (45% vs. 52%) seemed equivalent. Conclusions. This is the first long-term, randomized trial comparing enteric-coated mycophenolate sodium versus mycophenolate mofetil along with reduced maintenance tacrolimus dosing and steroid avoidance, which resulted in similarly low-BPAR rates, acceptably high renal function at 48 months, and an equivalent side effect profile.

BACKGROUND Given our previous experience using dual-induction therapy with antithymocyte globulin (ATG)/daclizumab (Dac) (each with fewer doses than if used alone), we chose to compare two distinct dual-induction strategies. METHODS Single-center, open-label randomized trial of 200 primary kidney transplant recipients was performed: (group I, n=100) ATG/Dac (3 ATG, 2 Dac doses) versus (group II, n=100) ATG/alemtuzumab (1 dose each), with maintenance consisting of reduced tacrolimus dosing (rTd), enteric-coated mycophenolate sodium (EC-MPS), and early corticosteroid withdrawal. One half of standard EC-MPS dosing was targeted in group II to avoid severe leukopenia previously seen with alemtuzumab. The goal in both arms was to achieve rapid and effective lymphocyte depletion while simultaneously allowing reduced maintenance immunosuppression. Primary endpoint was the incidence of biopsy-proven acute rejection (BPAR). RESULTS With median follow-up of 38 months, there were no differences in BPAR rates: 14 of 100 vs. 13 of 100 (including borderline) and 10 of 100 vs. 9 of 100 (excluding borderline) in groups I and II, respectively (nonsignificant). Actuarial patient/graft survival at 48 months was 96%/91% in group I vs. 92%/83% in group II (N.S.). Mean estimated glomerular filtration rate (±standard error) at 36 months was 72.1±3.3 vs. 67.5±3.3 in groups I and II (N.S.). Greater incidence of leukopenia occurred in group II at month 1 only (P=0.002). Percentages having EC-MPS withheld/discontinued due to leukopenia, gastrointestinal symptoms, and infection were 12 of 100, 7 of 100, and 0 of 100 in group I vs. 19 of 100, 0 of 100, and 2 of 100 in group II, respectively (P=0.01). Rates of new onset diabetes mellitus after transplantation and infections were equally low in both groups (no lymphoproliferative disorders were observed). CONCLUSIONS These two distinct dual-induction therapies with rTd, EC-MPS, and planned early corticosteroid withdrawal resulted in favorable rates of BPAR and all secondary outcomes.

Author(s): Burke, George W; Chang, Jei-Wen; Pardo, Victoriano; Sageshima, Junichiro; Chen, Linda; Ciancio, Gaetano; Tsai, Hsin-Lin; Wei, Changli; Fornoni, Alessia

Background. Hypothermic machine perfusion (MP) preservation is used for all deceased donor kidney transplants at our center. Kidneys are placed in cold storage at retrieval, then transferred to MP on arrival. Because a lack of consensus regarding optimal use of MP still exists, we evaluated the overall impact of using MP at our center and the prognostic value of MP (Pump) time. Methods. We retrospectively analyzed 339 adult, primary deceased donor kidney transplant recipients who were pooled across three prospective, randomized immunosuppression trials (since 2000) at our center. In addition to providing overall results for delayed graft function (DGF) (requirement for dialysis in the first week), slow graft function (SGF), first biopsy-proven acute rejection (BPAR), and graft failure, stepwise logistic and Cox regression analyses were used to determine the prognostic value of pump time, particularly after controlling for other significant prognosticators. Results. Mean cold storage and pump times were 6.6 and 26.7 hr, consistent across immunosuppression protocols. Overall DGF and SGF rates were 4.4% (15/339) and 12.1% (41/339). DGF was equally low for pump time less than 24 vs. more than or equal to 24 hr, 5.2% (6/116) vs. 4.0% (9/223) (P=0.63), with similar results after adjusting for known DGF predictors. A significantly lower first BPAR rate was observed for longer pump time (as a continuous variable) among more immunologically active recipients (those having more risk factors: DGF, age