Tacrolimus‐ versus sirolimus‐based immunosuppression after simultaneous pancreas and kidney transplantation: 5‐year results of a randomized trial

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and ‐kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open‐label, randomized, monocentric, 5‐year follow‐up study, a tacrolimus‐ and a sirolimus‐based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti‐thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval ?4.61% to 4.61%) and 6% (90% confidence interval ?6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty‐four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).     

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged‐release tacrolimus plus mycophenolate mofetil or sirolimus

ADHERE was a randomized, open‐label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolonged‐release tacrolimus‐based immunosuppressive regimens. On Days 0–27, patients received prolonged‐release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged‐release tacrolimus plus MMF (Arm 1) or prolonged‐release tacrolimus (≥25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full‐analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m²; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged‐release tacrolimus plus MMF (Arm 1) versus lower dose prolonged‐release tacrolimus plus sirolimus (Arm 2).     

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation

Early conversion to a calcineurin‐inhibitor (CNI)‐free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1‐year renal function as compared with a cyclosporine (CsA)‐based regimen (SMART core‐study). This observational follow‐up describes 132 patients followed up within the SMART study framework for 36 months. At 36 months, renal function continued to be superior in SRL‐treated patients [ITT‐eGFR_@36m: 60.88 vs. 53.72 (CsA) ml/min/1.73 m², P = 0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36 months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA‐treated patients. In a multivariate analysis, donor age >60 years, S‐creatinine at conversion >2 mg/dl, CMV naïve(‐) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36 months. Early conversion to a CNI‐free SRL‐based immunosuppression is associated with a sustained improvement of renal function up to 36 months after transplantation. Patient selection will be key to derive long‐term benefit and avoid treatment failure using this mTOR‐inhibitor‐based immunosuppressive regimen.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).     

Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor‐specific anti‐HLA antibodies: a cohort study

The development of de novo anti‐HLA donor‐specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. Despite this, antibody screening post‐transplant is not widespread, largely because the optimal management of patients with dnDSA remains undetermined. We hypothesized that in this population, calcineurin inhibitor blood levels would be an independent predictor of graft loss. We analyzed a cohort of unsensitized patients for whom anti‐HLA antibody screening was performed prospectively post‐transplant. During the screening period between January 2005 and April 2016, 42 patients developed dnDSA. There was no difference in the clinical characteristics or the histological scores of patients biopsied for clinical indication versus those biopsied solely due to detection of dnDSA. Cox modeling revealed a strong relationship between mean tacrolimus levels following dnDSA detection and graft loss, with a hazard ratio of 0.49 (95% CI, 0.33–0.75), which persisted following adjustment for established independent predictors (HR, 0.52, 95% CI, 0.30–0.89). Kaplan–Meier analysis by tertiles of tacrolimus levels and receiver operating curve analysis concurred to show that a threshold of 5.3 ng/ml could be predictive of graft loss. These data suggest that anti‐HLA antibody monitoring post‐transplant could guide maintenance immunosuppression and improve graft outcomes.     

A randomized,controlled trial of everolimus‐based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor‐based immunosuppression incur increased long‐term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36‐month, prospective, multinational, open‐label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI‐WD); everolimus with mycophenolate and steroid withdrawal (steroid‐WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI‐WD versus control was 65.1 ml/min/1.73 m² vs. 67.1 ml/min/1.73 m² by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI‐WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow‐up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.     

Ten‐year observational follow‐up of a randomized trial comparing cyclosporine and tacrolimus therapy combined with steroid withdrawal in living‐donor renal transplantation

Although various strategies for steroid withdrawal after transplantation have been attempted, there are few reports of the long‐term results of steroid withdrawal regimens in kidney transplantation. Earlier, we reported on a 5‐year prospective, randomized, single‐center trial comparing the safety and efficacy of cyclosporine (CsA) plus mycophenolate mofetil (MMF) with that of tacrolimus (TAC) plus MMF, when steroids were withdrawn 6 months after kidney transplantation in low‐risk patients. We now report the 10‐year observational data on the study population. We collected data from the database of the Organ Transplantation Center, Samsung Medical Center for 5 years after completion of the original study (TAC group n = 62; CsA group n = 55). The 10‐year patient survival, death‐censored graft survival, and acute rejection‐free survival did not differ between groups (98% vs 96%; P = 0.49, 78% vs 85%; P = 0.75 and 84% vs 76%; P = 0.14 in the TAC group vs CsA group, respectively). In low‐risk patients, there was no difference in long‐term patient and graft survival between TAC‐ and CsA‐based late steroid withdrawal regimens that included MMF treatment. More long‐term randomized clinical trials are needed to clarify the benefits of late steroid withdrawal in kidney transplantation.     

An open-label randomized trial of the safety and efficacy of sirolimus vs. azathioprine in living related renal allograft recipients receiving cyclosporine and prednisone combination

BACKGROUND: The ability of sirolimus (SRL), in combination with reduced exposure of cyclosporine, was investigated to prevent acute rejection and associated side effects. METHODS: Between June 1999 and February 2000, 70 recipients of primary one-haplotype living-related donor renal allografts were randomized to receive SRL (2 mg/d) or azathioprine (AZA) (2 mg/kg/d) combined with cyclosporine and prednisone. The primary end-point was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 3 months after transplantation. RESULTS: From week 4 to month 12, SRL patients received lower cyclosporine (week 4: 364 mg/d vs. 455 mg/d, p = 0.004; month 12: 195 mg/d vs. 255 mg/d, p = 0.038) doses and showed lower cyclosporine concentrations (week 4: 247 ng/mL vs. 309 ng/mL, p = 0.04; month 12: 143 ng/mL vs. 188 ng/mL, p = 0.045). Compared with AZA, SRL patients showed reduced 3-month primary end point (0% vs. 17.1%, p = 0.025), and reduced incidence of biopsy-confirmed acute rejection at 3 months (0% vs. 14.3%, p = 0.01) but not at 12 months (11.4% vs. 14.3%, NS). Mean creatinine at 12 months were not different (1.8 +/- 0.6 vs. 1.6 +/- 0.6, p = 0.23). Hyperlipidemia was the only adverse event more frequent among SRL patients (49% vs. 17%, p = 0.01). There were no differences in infections and no malignancies in both groups. CONCLUSIONS: The combination of 2 mg fixed doses of SRL, reduced cyclosporine exposure and prednisone was associated with a low incidence of acute rejection and did not result in significantly impaired graft function compared with patients receiving AZA, standard doses of cyclosporine and prednisone.     

Long-term results of a prospective randomized trial comparing tacrolimus versus cyclosporine in African– American recipients of primary cadaver renal transplant

The ideal immunosuppressive treatment for African-American kidney transplant recipients has not been established. We performed a long-term prospective randomized trial comparing the results of tacrolimus (TAC) and cyclosporine (CSA) in the African-American population. Thirty-five African-American primary cadaveric renal transplant (CRT) recipients were enrolled in the study. Group I (n = 14) received TAC and group II (n = 21) received CSA; mean follow up was 78 months. We found no difference in patient/graft survival rates between the groups. Twelve patients in the CSA group were converted to TAC, mostly because of hypercholesterolemia or as a rescue for an acute rejection episode. Significant lower creatinine and cholesterol levels were seen at 1 year post-transplant, but this difference lost significance at 3 and 5 years, possibly because of conversion of most patients from CSA to TAC. In conclusion, African-American recipients of primary CRTs can achieve excellent long-term results with TAC-based immunosuppression.     

Chronic‐active antibody‐mediated rejection with or without donor‐specific antibodies has similar histomorphology and clinical outcome – a retrospective study

Chronic‐active antibody‐mediated rejection (c‐aABMR) is defined as histological evidence of chronic endothelial injury (cg), also known as transplant glomerulopathy, and either microvascular inflammation (MVI) or positivity for C4d. Importantly, the presence of donor‐specific antibodies (DSA) is currently still mandatory for the diagnosis of c‐aABMR. This retrospective study of 41 c‐aABMR patients investigates whether cases suspicious for c‐aABMR (DSA negative, n = 24) differ from cases of c‐aABMR (DSA positive, n = 17) with respect to renal histology, allograft function and long‐term graft survival. All included patients had progressive loss of allograft function and were diagnosed by for cause biopsy and scored according to the Banff ’15 criteria. In all DSApos cases, DSA were de novo and the majority was directed against HLA‐II being mostly anti‐HLA‐DQ antibodies. There were no statistically significant differences in clinical characteristics, decline in allograft function and renal allograft survival in cases with or without DSAs. All cases showed chronic histomorphological damage and inflammation, irrespective of the presence of DSA. Renal histology and clinical outcome of patients suspicious for c‐aABMR (DSAneg) do not significantly differ from patients with a diagnosis of c‐aABMR (DSApos). We believe that our study adds to the ongoing debate regarding the need for DSAs to be present for the diagnosis of c‐aABMR.     

Long‐term outcome of belatacept therapy in de novo kidney transplant recipients – a case‐match analysis

While belatacept has shown favorable short‐ and midterm results in kidney transplant recipients, only projections exist regarding its potential impact on long‐term outcome. Therefore, we performed a retrospective case‐match analysis of the 14 belatacept patients originally enrolled in the phase II multicenter trial at our center. Fifty six cyclosporine (CyA)‐treated patients were matched according to age at transplantation, first/retransplant, and donor type. Ten years after kidney transplantation, kidney function remained superior in belatacept‐treated patients compared with the CyA control group. Moreover, none of the belatacept‐treated patients had donor‐specific antibodies ≥10 years post‐transplantation compared with 38.5% of tested CyA‐treated subject (0/10 vs. 5/13; P = 0.045). Notably, however, patient and graft survival was virtually identical in both groups (71.4% vs. 71.3%; P = 0.976). In the present single‐center study population, patients treated with belatacept demonstrated a patient and graft survival at 10 years post‐transplant which was comparable to that of similarly selected CNI‐treated patients. Larger studies with sufficient statistical power are necessary to definitively determine long‐term graft survival with belatacept.     

Sirolimus vs mycophenolate mofetil (MMF) in primary combined pancreas and kidney transplantation. Results of a long‐term prospective randomized study

The study was intended to compare pancreas graft survival rates in two groups of pancreas and kidney transplant recipients prospectively randomized to treatment either with sirolimus or MMF. From 2002 to 2013, 238 type 1 diabetic recipients with end‐stage kidney disease were randomized 1:1 to sirolimus or MMF treatment. Noncensored pancreas survival at 5 years was 76.4 and 71.6% for sirolimus and MMF groups, respectively (P > .05). Death‐censored pancreas survival was better in the sirolimus group (P = .037). After removal of early graft losses pancreas survival did not differ between groups (MMF 83.1% vs sirolimus 91.6%, P = .11). Nonsignificantly more grafts were lost due to rejection in the MMF group (10 vs 5; P = .19). Cumulative patient 5‐year survival was 96% in the MMF group and 91% in the sirolimus group (P > .05). Five‐year cumulative noncensored kidney graft survival rates did not statistically differ (85.6% in the sirolimus group and 88.8% in MMF group). Recipients treated with MMF had significantly more episodes of gastrointestinal bleeding (7 vs 0, P = .007). More recipients in the sirolimus group required corrective surgery due to incisional hernias (21 vs 12, P = .019). ClinicalTrials No.: NCT 03582878.     

Factors at de novo donor‐specific antibody initial detection associated with allograft loss: a multicenter study

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor‐specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death‐censored allograft loss were assessed by Cox proportional modeling. Death‐censored allograft survival was 77.0% (87/113) during a median follow‐up of 2.2 (IQR 1.2–3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6–15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1–13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post‐transplant (years) until donor‐specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody‐mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.     

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.