In this 12‐month, multicenter, randomized, open‐label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low‐dose tacrolimus ...(EVR+LTac) or mycophenolate mofetil plus standard‐dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti‐thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy‐proven acute rejection tBPAR/graft loss/death/loss to follow‐up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% −3.0, 11.4). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow‐up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 22.0 vs. 63.1 19.5 mL/min/1.73 m2) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.
This 12‐month, multicenter, randomized, open‐label study in de novo renal transplant recipients reports statistically better graft survival, similar renal function, and comparable safety, despite missing the noninferiority margin of composite efficacy failure rate, with an everolimus plus low‐dose tacrolimus regimen versus mycophenolate mofetil plus standard dose tacrolimus.
Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice‐daily tacrolimus to a novel extended‐release once‐daily tacrolimus formulation ...(LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy‐proven acute rejection BPAR, or loss to follow‐up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4–15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once‐daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.
This phase III noninferiority conversion trial in stable renal transplant recipients demonstrates that a novel extended‐release once‐daily tacrolimus formulation is noninferior to tacrolimus twice‐daily in efficacy failure rates, has a similar safety profile, and requires lower doses to achieve target trough levels.
A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open‐label, ...noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low‐dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time‐normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy‐proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3–8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. Trial registration: NCT01025817.
This post hoc exploratory analysis of the US92 study assesses efficacy and safety events with specific everolimus and tacrolimus trough concentrations, and supports maintaining an everolimus trough concentration of 3–8 ng/mL when combined with low‐dose tacrolimus to achieve favorable efficacy and safety outcomes in renal transplant patients.
Sotrastaurin, a selective protein‐kinase‐C inhibitor, blocks early T‐cell activation through a calcineurin‐independent mechanism. In this study, de novo renal transplant recipients with immediate ...graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy‐proven acute rejection (BPAR), graft loss, death or lost to follow‐up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation SD) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m2, p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study‐medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin‐inhibitor‐free regimen of sotrastaurin+MPA versus the tacrolimus‐based control. Ongoing studies are evaluating alternative sotrastaurin regimens.
A calcineurin inhibitor‐free regimen including sotrastaurin, a novel small molecule inhibiting protein‐kinase C, is shown to be associated with insufficient efficacy, but better renal function, in patients on study drug compared with the control regimen. See editorial by Meier‐Kriesche and Kaplan on page 1355.
Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed‐dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and ...clinical endpoints of rejection and toxicity. This 2‐year, open‐label, randomized, multicenter trial compared the efficacy and safety of concentration‐controlled MMF (MMFCC) dosing with a fixed‐dose regimen in 720 kidney recipients. Patients received either (A) MMFCC and reduced‐level calcineurin inhibitor (MMFCC/CNIRL); (B) MMFCC and standard‐level CNI (MMFCC/CNISL); or (C) fixed‐dose MMF and CNISL (MMFFD/CNISL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (α= 0.05) of group A versus group C for treatment failure (including biopsy‐proven acute rejection BPAR, graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p ≤ 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMFCC with low‐dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMFFD, indicating potential utility of MMFCC in CNI‐sparing regimens.
In this randomized trial, concentration‐controlled dosing of mycophenolate mofetil with reduced doses of calcineurin inhibitors was not inferior to standard dosing.
The clinical significance of pre‐transplant donor‐specific antibodies (DSA), despite negative cytotoxicity and flow cytometry crossmatches (FCXMs), is unknown. We performed a retrospective cohort ...study of 60 living donor renal transplant recipients, all with pre‐transplant cytotoxicity and T‐cell and B‐cell FCXMs that were negative. Twenty recipients had pre‐transplant DSA detected by enzyme‐linked immunosorbent assays (ELISA) and/or microbead methods. Forty contemporaneous DSA‐negative controls were selected. In the DSA‐positive group, after a median follow‐up of 8.2 months (25–75% range, 5.4–22.8 months), patient survival was 100% and allograft survival was 95.0%. Acute humoral rejection (AHR) developed in four patients (20.0%). Three of the AHR episodes occurred within the first month post‐transplant. Median serum creatinine at last follow‐up was 1.3 mg/dL (25–75% range, 1.0–1.6 mg/dL), versus 1.1 mg/dL (25–75% range, 0.9–1.4 mg/dL) in the DSA‐negative controls (p = 0.29). Only one of the 40 controls developed AHR (2.5%). Pre‐transplant DSA was associated with a significantly increased incidence of AHR (p = 0.02 by log‐rank test). In conclusion, despite negative pre‐transplant cytotoxicity and FCXMs, renal transplant recipients with pre‐transplant DSA detected by solid‐phase methods may have an increased incidence of AHR and require close monitoring post‐transplant.
Renal transplant recipients with pre‐transplant donor‐specific antibodies detected by solid‐phase assays have an increased risk of acute antibody‐mediated rejection, despite negative pre‐transplant complement‐dependent cytotoxicity and flow cytometry crossmatches.
This randomized, pilot study compared the Janus kinase inhibitor CP‐690,550 (15 mg BID CP15 and 30 mg BID CP30, n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients ...received an IL‐2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP‐690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6‐month biopsy‐proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6‐month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by ≤77% in CP‐690,550‐treated patients. In the CP‐690,550 arms, there were modest lipid elevations and a trend toward more frequent anemia and neutropenia during the first 6 months. These data suggest that coadministration of CP‐690,550 30 mg BID with MMF is associated with overimmunosuppression. At 15 mg BID, the efficacy/safety profile was comparable to the tacrolimus control group, excepting a higher rate of viral infection. Further dose‐ranging evaluation of CP‐690,550 is warranted.
In this pilot study, inhibition of the JAK3 pathway with CP‐690,550 resulted in relatively low rates of rejection after kidney transplantation with evidence of over‐immunosuppression when CP‐690,550 30 mg BID was combined with MMF.
Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6‐month, multicenter, randomized, open‐label study of three ascending ...concentration‐controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low‐risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic–pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low‐dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high‐dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r2= 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6‐month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low‐ and medium‐exposure groups, and potentially associated with a reduced incidence of NODAT.
This 6‐month phase II dose‐ranging study after kidney transplantation shows that the novel calcineurin inhibitor voclosporin is as efficacious as tacrolimus in preventing acute rejection, results in similar renal function in the low‐ and medium‐exposure groups, and could potentially be associated with a reduced incidence of new onset of posttransplant diabetes.
We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated ...by nondirected donors, were identified using a computer algorithm incorporating virtual cross‐matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O‐patients receiving a transplant (n = 90) was greater than the number of blood type O‐non‐directed donors (n = 32) initiating chains. We have 1‐year follow up on the first 100 transplants. The mean 1‐year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts.
The authors report on the largest series of kidney chain transplants, which includes 54 nondirected donors and 272 recipients of whom 46% are ethnic minorities and 63% received shipped grafts from other centers.
Abstract Background Living donor kidney transplant (LDKT) can be impeded by multiple barriers. One possible barrier to LDKT is a large physical distance between the living donor's home residence and ...the procuring transplant center. Methods We performed a retrospective, single-center study of living kidney donors in the United States who were geographically distant (residing ≥150 miles) from our transplant center. Each distant donor was matched to 4 geographically nearby donors (<150 miles from our center) as controls. Results From 2007 to 2010, of 429 live kidney donors, 55 (12.8%) were geographically distant. Black donors composed a higher proportion of geographically distant vs nearby donors (34.6% vs 15.5%), whereas Hispanic and Asian donors composed a lower proportion ( P = .001). Distant vs nearby donors had similar median times from donor referral to actual donation (165 vs 161 days, P = .81). The geographically distant donors lived a median of 703 miles (25% to 75% range, 244 to 1072) from our center and 21.2 miles (25% to 75% range, 9.8 to 49.7) from the nearest kidney transplant center. The proportion of geographically distant donors who had their physician evaluation (21.6%), psychosocial evaluation (21.6%), or computed tomography angiogram (29.4%) performed close to home, rather than at our center, was low. Conclusions Many geographically distant donors live close to transplant centers other than the procuring transplant center, but few of these donors perform parts of their donor evaluation at these closer centers. Black donors comprise a large proportion of geographically distant donors. The evaluation of geographically distant donors, especially among minorities, warrants further study.
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