Lois Hanson

Randomized Trial of Mycophenolate Mofetil Versus Enteric-coated Mycophenolate Sodium in Primary Renal Transplant Recipients Given Tacrolimus and Daclizumab/thymoglobulin: One Year Follow-up

Background. It was of interest to compare enteric-coated mycophenolate sodium (EC-MPS) versus mycophenolate mofetil (MMF) among renal transplant recipients receiving a tacrolimus-based immunosuppressive regimen. Methods. Between December 2004 and February 2006, a single-center, open-label randomized trial of MMF (group A, n=75) versus EC-MPS (group B, n=75) was performed in primary renal transplant recipients receiving combined thymoglobulin/daclizumab induction along with reduced tacrolimus dosing and elimination of corticosteroids 1 week postoperatively. The primary endpoint was the incidence rate of acute rejection (AR) during the first 12 months posttransplant; secondary aims were to compare graft and patient survival, renal function, drug dosing and monitoring, gastrointestinal side effects, and other adverse events at 12 months of follow-up. Results. Patient/graft survival in groups A and B were 100%/96% versus 99%/96%, respectively (N.S.). At 12 months, a total of nine patients (6%) experienced biopsy-proven AR, 3% (2/75) vs. 9% (7/75) in the MMF and EC-MPS arms, respectively (N.S.). At 12 months, the geometric mean*/SE serum creatinine concentration and arithmetic mean±SE calculated glomerular filtration rate in groups A and B, respectively, were 1.30*/1.03 and 61.4±2.0 vs. 1.26*/1.03 and 66.0±2.1 (N.S.). Incidence of new onset diabetes mellitus (11% vs. 11%), infections requiring hospitalization (13% vs. 15%), and gastrointestinal side effects (36% vs. 32%) appeared equivalent (N.S.). Conclusions. Early efficacy and toxicity were equivalent between the two study arms. Optimizing either MMF or EC-MPS along with a combined thymoglobulin/daclizumab induction, low tacrolimus dosing and steroid avoidance resulted in a low AR rate and an acceptably high renal function at 12 months.

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation

The optimal long-term regimen for immunosuppression for kidney transplant recipients is unknown. We conducted a randomized trial involving 150 kidney transplant recipients to compare tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF), and cyclosporine/sirolimus. All patients received daclizumab induction and maintenance corticosteroids. Median follow-up was 8 yr post-transplant. Acute rejection (AR) occurred significantly less often among those treated with tacrolimus/MMF (12%) than among those treated with tacrolimus/sirolimus (30%) or cyclosporine/sirolimus (28%). Mean estimated GFR was consistently higher in the tacrolimus/MMF arm, especially after controlling for donor age in a multivariable model during the first 36 mo (P ≤ 0.008). The rate of dying with a functioning graft was significantly higher among those treated with tacrolimus/sirolimus (26%) than among those treated with tacrolimus/MMF (12%) or cyclosporine/sirolimus (4%). We did not observe significant differences in actuarial graft survival at 8 yr post-transplant between the groups. Patient noncompliance seemed responsible for 45% (13/29) of observed graft failures, with 11 of these occurring after 36 mo. Significantly more viral infections, protocol violations, and need for antilipid therapy occurred among patients receiving sirolimus, but we did not observe differences between the groups with regard to infections requiring hospitalization or new-onset diabetes. Taken together, these results suggest that maintenance therapy with tacrolimus/MMF is more favorable than either tacrolimus/sirolimus or cyclosporine/sirolimus.

Graft failure due to noncompliance among 628 kidney transplant recipients with long-term follow-up: a single-center observational study.

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<0.000001 each) and non-white recipient (P=0.004 and P=0.02). Estimated percentages of ever developing GFNC were 28.4%±6.5% among 79 non-whites younger than 35 years versus 0.0% (0/144) among whites 50 years or older. Among 302 recipients younger than 50 years, 18.1%±4.1% developed GFNC, representing 67.6% (25/37) of its death-censored graft failures observed beyond 24 months after transplant. Conclusions GFNC is a major cause of late GF at our center, with younger and non-white recipients at a significantly greater GFNC risk. Interventional approaches to eliminate GFNC could dramatically improve long-term kidney graft survival.

Randomized trial of thymoglobulin versus alemtuzumab (with lower dose maintenance immunosuppression) versus daclizumab in living donor renal transplantation

BACKGROUND We performed a randomized trial evaluating alemtuzumab, a humanized anti-CD52 monoclonal antibody, in living donor (LD) kidney transplantation. METHODS Thirty-eight LD first renal transplant recipients were randomized into three single-agent antibody induction groups: thymoglobulin (group A); alemtuzumab (group B); and daclizumab (group C). In groups A and C, target tacrolimus trough levels were 6 to 8 ng/mL, with 1 gm mycophenolate mofetil (MMF) administered twice daily, and maintenance methylprednisolone. In group B, the target tacrolimus trough level was 4 to 6 ng/mL, with 500 mg MMF administered twice daily, without methylprednisolone. RESULTS With 29/38 patients now followed beyond 36 months posttransplantation, we observed no graft failures and only one death with a functioning graft (in group B). Acute rejection episodes were low: 0/13, 1/13, and 1/12 patients in groups A, B, and C. Biopsy-proven chronic allograft injury was higher among group B (3/13) versus groups A (0/13) or C (0/12; P = .01). Poorer renal function was observed in group B; the mean calculated creatinine clearance at 3 months posttransplantation was significantly poorer: 63.3 ± 3.0 versus 85.4 ± 7.2 and 82.2 ± 8.2 in groups A and C (P = .01). No differences in the incidence of adverse events were observed.

Favorable outcomes with machine perfusion and longer pump times in kidney transplantation: a single-center, observational study.

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 <50 yr, and non-white) (univariable P=0.005; multivariable P=0.009), with an estimated hazard ratio of 0.43 (P=0.006) favoring pump time more than or equal to 24 hr among those with more than or equal to two risk factors. Conclusions. In this single-center, observational study, MP with prolonged pump times was associated with low DGF/SGF and first BPAR rates, supporting continued use of MP.

Randomized trial of three induction antibodies in kidney transplantation: long-term results.

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.

Advantage of Rapamycin Over Mycophenolate Mofetil When Used With Tacrolimus for Simultaneous Pancreas Kidney Transplants: Randomized, Single‐Center Trial at 10 Years

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end‐stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long‐term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low‐dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy‐proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c‐peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10‐year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent.

Randomized trial of dual antibody induction therapy with steroid avoidance in renal transplantation.

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.

Randomized Trial of Mycophenolate Mofetil Versus Enteric-Coated Mycophenolate Sodium in Primary Renal Transplantation With Tacrolimus and Steroid Avoidance: Four-Year Analysis

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.

Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation

Although antibody induction has gained in popularity, two agents are rarely combined. We retrospectively analyzed peripheral lymphocyte phenotypes of renal transplant recipients who received induction therapy with a different antibody/combination: alemtuzumab(C1H), Thymoglobulin(rATG), daclizumab(Dac), rATG+C1H, and rATG+Dac. CD4+ T-cells were suppressed by C1H and rATG+C1H, as well as by rATG and rATG+Dac but to a lesser extent. The effect lasted for 3 years at around 40% of baseline values. CD8+ T-cells showed a similar trend but had a more rapid recovery to baseline. CD19+ B-cells were effectively suppressed for 2 months by C1H and rATG+C1H, and abruptly returned to baseline afterwards; suppression by rATG(7 doses) was modest but lasted longer. A higher proportion of CD56+CD16+ Natural Killer cells in C1H treated patients suggested a relatively spared effect of C1H on this cell type. Low CD25+ T-cells by 5-dose Dac returned to baseline around 6 months, whereas rATG+C1H and rATG+Dac showed persistent effect. CD4+CD25hi T-cells were suppressed by both rATG+C1H and rATG+Dac, but the initial proportion of CD4+CD25hi T-cells among CD4+ T-cells and CD4+CD25hi/CD4+CD25lo ratio were significantly higher in rATG+C1H. Overall, with extensive and persistent lymphocyte suppression by a simple administration of agents, single-dose rATG+C1H induction can be an alternative in renal transplantation.