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Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: A Randomized Clinical Trial

Open AccessPublished:November 17, 2022DOI:https://doi.org/10.1016/j.xkme.2022.100574

      ABSTRACT

      Rationale & Objective

      In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective is to compare calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.

      Study Design

      Prospective, randomized, open label, parallel group, investigator-initiated, international multi-center trial.

      Setting & Participants

      KTRs aged 18–80 years with a stable graft function (estimated glomerular filtration rate [eGFR] >20 mL/min per 1.73 m2), 3–60 months post-transplantation treated with tacrolimus or Cyclosporine A were eligible for inclusion.

      Intervention

      Continuation with a CNI-based regimen or switch to belatacept for 12 months.

      Outcomes

      Comparison of the change in estimated 7-year risk of major adverse cardiovascular events (MACE) and all-cause mortality, changes in traditional markers of cardiovascular health, as well as measures of arterial stiffness.

      Results

      In the 105 KTRs randomized, we found no differences between the treatment groups in predicted risk for MACE or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor® device and peripherally, was lower after belatacept treatment compared with CNI. The mean changes in traditional CV risk factors, including kidney transplant function, were otherwise similar in both treatment groups. The belatacept group had four acute rejection episodes; two were severe rejections, of which one led to graft loss.

      Limitations

      Heterogeneous baseline eGFR and time from transplantation to trial enrolment in the participants. Limited study duration of 1 year.

      Conclusions

      We found no effects on calculated CV risk by switching to belatacept treatment. Participants in the belatacept group had lower central and peripheral diastolic blood pressure, but also a higher rejection rate, in the belatacept group.

      Keywords

      INTRODUCTION

      The risk of cardiovascular disease (CVD) in patients with kidney failure is much higher than in the general population across all age groups
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      . Managing a transplanted patient should therefore include CV risk reduction measures to improve both graft and patient outcomes. Current guidelines for prevention of CVD are based upon data from the general population and from studies specifically targeting CVD in KTRs
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      . In addition to addressing traditional risk factors for CVD, such as lifestyle choices, hypertension, hyperlipidemia, and diabetes, KTRs present two potentially modifiable factors: kidney graft function and type of immunosuppressive maintenance regimen.
      First, evidence indicates that declining graft function and graft loss are potentially modifiable risk factors for CVD and all-cause mortality in this population, which make strategies for optimizing graft function important
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      . Second, among immunosuppressive drugs used for transplantation, both steroids and calcineurin inhibitors (CNIs) are associated with adverse CV side effects
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      . Therefore, attempts have been made to minimize or eliminate their use. While these have led to reasonably safe steroid-free regimens
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      , CNIs are still the cornerstone of immunosuppression in modern solid organ transplantation. Early graft survival improved greatly after the introduction of cyclosporine (CsA) in the early 1980s
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      , and tacrolimus (TAC) has been the CNI of choice since the 1990s

      Ong SC, Gaston RS. Thirty Years of Tacrolimus in Clinical Practice. Transplantation. 2020;Publish Ahead of Print.

      . Despite the benefits of CNIs in the early post-transplant period, they have dose-dependent side effects, including post-transplant diabetes mellitus, hypertension, hypercholesterolemia, and nephrotoxicity, leading to progressive decline in kidney graft function
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      The natural history of chronic allograft nephropathy.
      . Therefore, there is an ongoing incentive for development of novel immunosuppressive agents without the side effects of CNIs.
      Belatacept, a modified form of CTLA4-Ig, binds to CD80 and CD86 on antigen presenting cells, thus blocking CD28 mediated co-stimulation of T-cells. The BENEFIT trials have shown promise for belatacept as an option in designing a more favorable immunosuppressive regimen
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      • et al.
      A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study).
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      • et al.
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      • et al.
      Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies.
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      • et al.
      A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).
      • Vincenti F.
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      • et al.
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      . In brief, despite higher rates of early rejection, the relative risk of death or graft loss after 7 years was reduced by 43% in patients treated with belatacept versus CsA-treated patients, and eGFR in the belatacept-group was on average 22 ml/min/1.73m
      • Jardine A.G.
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      • Holdaas H.
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      higher than in the CsA-group. Furthermore, in a meta-analysis comparing belatacept with CNIs, treatment with belatacept was associated with lower blood pressure, lower incidence of diabetes and a more favorable lipid profile
      • Masson P.
      • Henderson L.
      • Chapman J.R.
      • Craig J.C.
      • Webster A.C.
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      .
      However, it is not yet proven whether these findings translate into overall CVD reduction. Soveri et al. have previously developed a risk calculator for CVD and all-cause mortality for use in KTRs
      • Soveri I.
      • Holme I.
      • Holdaas H.
      • Budde K.
      • Jardine A.G.
      • Fellstrom B.
      A cardiovascular risk calculator for renal transplant recipients.
      . The group later used the data of the BENEFIT and BENEFIT-EXT trials to calculate the potential benefit associated with belatacept treatment and found a substantial calculated 7-year risk reduction for major adverse cardiac endpoints (MACE) and mortality by converting from CsA to belatacept
      • Soveri I.
      • Snyder J.
      • Holdaas H.
      • et al.
      The external validation of the cardiovascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials.
      .
      A shortcoming of belatacept that has hindered its implementation in kidney transplantation has been the relatively high rate of early rejection, as well as the lack of studies comparing its efficacy with low-dose TAC, the current standard of care in KTRs. In the present study, our aim was to investigate 1) the effects of conversion from a low-dose CNI-based therapy to belatacept on estimated risk of CVD and all-cause mortality by using the aforementioned risk calculator developed by Soveri et al., validated for use in KTRs
      • Soveri I.
      • Holme I.
      • Holdaas H.
      • Budde K.
      • Jardine A.G.
      • Fellstrom B.
      A cardiovascular risk calculator for renal transplant recipients.
      ,
      • Soveri I.
      • Snyder J.
      • Holdaas H.
      • et al.
      The external validation of the cardiovascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials.
      , and 2) the changes in traditional markers of cardiovascular health, as well as measures of arterial stiffness.

      METHODS

      Study design

      This was a prospective, randomized, open label, parallel group, investigator-initiated, international multi-center trial (EudraCT no. 2013-001178-20). Patients were randomized in 1:1 ratio to either continue treatment with a CNI-based regimen or to switch to belatacept for a study duration of 12 months. An open design was chosen since CNIs were given as tablets daily and belatacept was administered as infusion every four weeks.
      Patients were recruited from 9 transplant centers in Denmark, the Netherlands, Norway, and Sweden. KTRs aged 18–80 years with a stable graft function (estimated glomerular filtration rate [eGFR] >20 mL/min per 1.73 m2), 3–60 months post-transplantation treated with TAC or CsA were eligible for inclusion. Patients were excluded if they were Epstein-Barr virus (EBV) IgG seronegative, had severe de novo or recurrent kidney disease, had a history of vascular or antibody-mediated rejection in the present transplant or had a history of recent malignancy.
      The study was approved by the local ethics committees. Written informed consent was obtained from all patients, and the trial was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.

      Study medication

      For patients randomized to the study arm with belatacept, the previous CNI treatment (TAC or CsA) was tapered in the initial period as follows: 100% on day 1, to 70-80% on day 7, to 40-60% on day 15, 20-30% on day 23 and none on day 29 and beyond. Belatacept was dosed 5 mg/kg IV on day 1, 15, 29, 43, 57 and then every month thereafter in the 12-month study period (Figure 1). Patients randomized to the control group with continuation of CNI treatment were to maintain trough levels of CsA between 75 and 200 ng/ml and TAC between 5 and 10 ng/ml. Both groups were to continue their underlying immunosuppressive regimen, consisting of mycophenolate mofetil (MMF) or mammalian target of rapamycin inhibitor and corticosteroids. Any other concomitant medication necessary to maintain the patients’ baseline condition or to treat a coexisting disease was permitted. Control of blood pressure, glucose and lipid parameters was left to the treating physicians, according to local practice.

      Efficacy assessment and procedures

      The primary endpoint of this trial was estimated CV risk using a prediction model developed for KTRs by Soveri et al.
      • Soveri I.
      • Holme I.
      • Holdaas H.
      • Budde K.
      • Jardine A.G.
      • Fellstrom B.
      A cardiovascular risk calculator for renal transplant recipients.
      ,
      • Soveri I.
      • Snyder J.
      • Holdaas H.
      • et al.
      The external validation of the cardiovascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials.
      . The prediction model was constructed based on the Assessment of Lescol in Renal Transplantation (ALERT) extension trial data
      • Jardine A.G.
      • Fellstrom B.
      • Logan J.O.
      • et al.
      Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study.
      , and later validated with the Patient Outcomes in Renal Transplantation (PORT) clinical database
      • Israni A.K.
      • Snyder J.J.
      • Skeans M.A.
      • et al.
      Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study.
      .
      The estimated 7-year risk of MACE and all-cause mortality in the two treatment groups were calculated as a linear combination of the following variables: age, previous coronary heart disease, previous smoker, current smoker, creatinine, diabetes mellitus, low-density lipoprotein (LDL), number of transplants and total time on kidney replacement therapy (Figure 2). Secondary endpoints were arterial stiffness, traditional CVD risk factors in KTRs (blood pressure, lipid profiles and eGFR), acute rejections, allograft loss, CV events and patient survival. Blood samples were drawn at a fasting state in the morning at baseline and at end of study visits for measurement of kidney function and CV biomarkers: creatinine, high-sensitivity C-reactive protein (hs-CRP), total cholesterol, high-density lipoprotein cholesterol (HDL-cholesterol), LDL cholesterol, triglycerides, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1). Arterial stiffness was assessed at the same time points by measuring central pulse pressure, pulse wave velocity and augmentation index using the SphygmoCor® method
      • Butlin M.
      • Qasem A.
      Large Artery Stiffness Assessment Using SphygmoCor Technology.
      .
      Figure thumbnail gr2
      Figure 2Cardiovascular risk calculator for kidney transplant recipients (Soveri et al., 2012)., List of variables used in the cardiovascular risk calculator. *Includes post-transplant diabetes mellitus. RRT = renal replacement therapy (including dialysis and transplantation)

      Sample size and randomization

      We performed a power calculation hypothesizing that the intervention arm would decrease the risk of MACE by 30%. We came to that estimate by extrapolation of the reduction in calculated risk in the previously mentioned paper by Soveri e.a.
      • Soveri I.
      • Snyder J.
      • Holdaas H.
      • et al.
      The external validation of the cardiovascular risk equation for renal transplant recipients: applications to BENEFIT and BENEFIT-EXT trials.
      ; the calculated risk of MACE for BENEFIT-patients decreased by 31.2% (from 14.3% to 10.9%), and for mortality by 40% (17.5% to 12.5%). The corresponding risk reduction for BENEFIT-EXT-patients was 27.8% (22.5 to17.6%) and 22.6% (30.9% to 25.2%). For a two-sample t-test on a two-sided significance level of 0.05, assuming a standard deviation of 0.64 (on the natural logarithmic scale), a sample size of 51 per group was required to obtain a power of 0.8 (80%) to detect a 30% calculated risk reduction in MACE. The ANCOVA model was expected to have slightly greater power than the two-sample t-test, and therefore a sample size of 102 patients was seen as sufficient for this study. To account for 8% drop-out, a total of 110 patients, 55 per treatment arm were included in the study. Randomization to treatment arm was performed using a computerized procedure, stratified by center, in a 1:1 ratio.

      Statistical analysis

      Due to a skewed distribution, the primary variable (estimated risk for MACE and morality) was log-transformed (natural logarithm). The primary endpoint was the comparison of the log of estimated MACE and mortality risk between treatment groups (CNI- vs. belatacept-based immunosuppression) at one year. For patients who discontinued the study before one year, the last available estimate of CV risk was used in the analysis of the intention-to-treat (ITT) population.
      The primary analysis on the primary endpoint was performed using analysis of covariance (ANCOVA) with treatment as a group variable and baseline log risk for MACE and mortality and center as covariates. All other comparisons on primary and secondary endpoints were based on ITT comparisons of treatment groups using two-sample t-test, or ANCOVA with correction for baseline variables and/or center. A two‐sided P value of <0.05 was considered statistically significant. Analyses were performed using SAS® version 9.4 (SAS Institute, Cary, NC).

      RESULTS

      Study participants and characteristics

      A total of 112 patients from 9 centers signed the patient informed consent form. Of these, one patient was a screen failure (history of rejection) and was never randomized. Of the 111 randomized patients, 6 withdrew consent before any study drug was given, 4 in the belatacept arm and 2 in the CNI arm. Thus, 105 patients were administered study medication: 54 in the belatacept arm and 51 in the CNI arm (defining our ITT population). In the belatacept-arm 5 patients were withdrawn from the study; 3 due to adverse events (AEs), 1 withdrew consent and 1 moved out of the country. Similarly, there were 2 withdrawals in the CNI arm; 1 due to AE and 1 withdrew consent. The remaining 49 patients in each treatment arm were defined as the per protocol (PP) population (Figure 3). As the difference between the PP population and the ITT population was quite small, we did not perform PP analyses to avoid the risk of type I error caused by multiple comparisons. The first patient was enrolled September 18th, 2014, and the last patient completed the study on September 13th, 2018. Baseline demographic data and clinical characteristics for each group are presented in Table 1.
      Table 1Baseline demographics and clinical characteristics (ITT population).
      Belatacept arm (n=54)CNI arm (n=51)
      Female13 (24%)13 (25%)
      Age, years55.0 (15.2)54.2 (13.8)
      BMI, kg/m226.1 (4.1)27.1 (4.1)
      Kidney replacement therapy
      Number of transplantations1 (1 - 2)1 (1 - 2)
      Time since last transplantation, months25.3 (3.7 - 59.6)23.4 (3.1 - 58.8)
      Total time on kidney replacement therapy, months35.6 (12.1 – 489.5)36.8 (5.3 - 220.8)
      Prior immunosuppressive therapy
      Tacrolimus53 (98%)48 (94%)
      Cyclosporine1 (2%)3 (6%)
      Steroids50 (93%)50 (98%)
      Mycophenolate50 (93%)47 (92%)
      mTOR inhibitor3 (6%)1 (2%)
      Baseline immunosuppression trough levels
      Tacrolimus5.8 (1.7)5.7 (1.7)
      Cyclosporine94 (4.8)89 (5.1)
      Cardiovascular medication
      ACE-inhibitors / angiotensin II antagonists39 (72%)29 (57%)
      Calcium channel blockers34 (63%)39 (77%)
      Diuretics16 (30%)15 (30%)
      α-adrenoceptor antagonists11 (20%)7 (14%)
      β-adrenoceptor antagonists29 (54%)27 (53%)
      Nitrate1 (2%)3 (6%)
      Statins27 (50%)32 (63%)
      Diabetes mellitus12 (22%)7 (14%)
      Hypertension30 (56%)33 (65%)
      Systolic blood pressure, mmHg137 (17.2)133 (18.4)
      Diastolic blood pressure, mmHg84 (9.7)81 (11.2)
      Smoking habits
      Non-smoker29 (54%)21 (41%)
      Current smoker6 (11%)8 (16%)
      Previous smoker19 (35%)22 (43%)
      Cardiovascular disease
      Peripheral vascular disease8 (15%)7 (14%)
      Previous heart failure2 (4%)3 (6%)
      Previous coronary heart disease4 (7%)6 (12%)
      Previous cerebrovascular disease2 (4%)4 (8%)
      Plasma creatinine, μmol/L135 (35.7)125 (42.6)
      eGFR (mL/min/1.73 m2)49.4 (14.8)56.6 (19.1)
      hs-CRP, mg/L3.1 (4.1)2.8 (2.8)
      Plasma glucose, mmol/L6.2 (1.8)5.9 (1.7)
      Total cholesterol, mmol/L5.0 (1.0)5.1 (1.0)
      HDL-cholesterol, mmol/L1.5 (0.5)1.6 (0.6)
      LDL-cholesterol, mmol/L2.7 (0.9)2.7 (0.9)
      Triglycerides, mmol/L1.9 (0.9)1.9 (0.9)
      Apolipoprotein B, g/L1.0 (0.4)1.0 (0.3)
      Apolipoprotein A1, g/L1.4 (0.3)1.5 (0.4)
      Data are presented as number (percentage) for categorical data, as mean value (standard deviation) for continuous variables and as median (min - max) for kidney replacement therapy.

      Estimated risk of MACE and mortality

      The primary endpoint was the estimated 7-year risk of MACE and all-cause mortality per the risk calculator developed by Soveri et al. (Figure 2). After 12 months of treatment, there was no statistically significant difference between the treatment groups in terms of change in predicted risk, neither for MACE nor for mortality (Table 2).
      Table 2Estimated 7-year risk of MACE and mortality.
      Belatacept armCNI armDifference
      BaselineEnd of studyBaselineEnd of study
      MACEMean (SD)0.15 (0.13)0.15 (0.15)0.14 (0.14)0.15 (0.15)
      Log mean risk change [95% CI]-2.31 [-2.40, -2.23]-2.25 [-2.33, -2.16]0.06 [-0.04, 0.16]
      MortalityMean (SD)0.21 (0.19)0.23 (0.20)0.19 (0.18)0.21 (0.19)
      Log mean risk change [95% CI]-1.94 [-1.96, -1.91]-1.92 [-1.94, -1.90]0.02 [-0.01, 0.05]
      MACE = major adverse cardiac event. CI = confidence interval
      In the belatacept-arm, mean (SD) estimated 7-year risk of MACE at baseline was 0.15 (0.13), and it remained unchanged after 1 year to 0.15 (0.15). Similarly, the risk estimation for the CNI continuation arm was 0.14 (0.14) at baseline and 0.15 (0.15) after 1 year. After applying the ANCOVA models and adjusting for hospital centers, the log mean risk prediction decreased by 2.31 (95% CI: 2.23, 2.40) for the belatacept-group, and 2.25 (95% CI: 2.16, 2.33) for the CNI group. The difference between interventions in log mean risk prediction for MACE was 0.06 (95% CI: -0.04, 0.16).
      The estimated 7-year mortality risk in the belatacept-arm at baseline was 0.21 (0.19), which increased non-significantly to 0.23 (0.20) after 1 year. Correspondingly for the CNI continuation arm, the predicted risk of mortality was 0.19 (0.18) at baseline and increased non-significantly to 0.21 (0.19) after 1 year. After applying the ANCOVA models and adjusting for hospital centers, the log mean risk prediction decreased by 1.94 (95% CI: 1.91, 1.96) for the belatacept-group, and 1.92 (95% CI: 1.90, 1.94) for the CNI group. The difference between interventions in log mean risk prediction for mortality was 0.02 (95% CI: -0.01, 0.05). An overview of the variables used in the risk calculation is presented in Table 3.
      Table 3Overview of variables composing estimated cardiovascular risk.
      Belatacept armCNI arm
      Risk calculator compositeVariableBaselineEnd of studyBaselineEnd of study
      Common for MACE and mortalityAge, years54.5 (15.2)55.5 (15.2)53.8 (13.7)54.8 (13.7)
      Creatinine, μmol/L135.1 (35.7)132.2 (44.1)124.7 (42.6)119.1 (38.4)
      Diabetes mellitus12 (22.2%)12 (22.2%)7 (13.7%)7 (13.7%)
      Coronary HD4 (7.4%)4 (7.4%)6 (11.8%)6 (11.8%)
      Current smoker6 (11.1%)6 (11.1%)8 (15.7%)8 (15.7%)
      Previous smoker19 (35.2%)19 (35.2%)22 (43.1%)22 (43.1%)
      MACE onlyLDL-cholesterol, mmol/L2.7 (0.9)2.6 (1.0)2.7 (0.9)2.6 (0.8)
      Number of transplants: 151 (94.4%)51 (94.4%)48 (94.1%)48 (94.1%)
      Number of transplants: 23 (5.6%)3 (5.6%)3 (5.9%)3 (5.9%)
      Mortality onlyTotal time KRT, months51.4 (69.5)62.9 (69.6)45.1 (37.0)56.9 (37.0)
      Data are presented as number (percentage) for categorical data and mean value (standard deviation) for continuous variables. HD = Heart Disease. MACE = major adverse cardiac event. KRT = kidney replacement therapy.
      Subgroup analysis was also performed to investigate whether time since transplantation influenced the results in risk calculation. Treatment arms were divided upon the median time after transplantation, thus creating an early and late group (before and after 26 months). There was no difference between belatacept and CNI in calculated risk of MACE (p = 0.33) and mortality (p = 0.56) in the subgroups.

      Traditional CVD risk factors

      The changes in traditional CV biomarkers from baseline to end of study are presented in Table 4. The mean changes were similar between the treatment groups, except for a significant difference in diastolic blood pressure, with lower levels after belatacept treatment compared with CNI. Systolic blood pressure showed a similar reduction, but the difference was not statistically significant.
      Table 4Change from baseline for traditional CVD risk factors.
      Risk factorBelatacept armCNI armDifferencep-value
      Systolic BP, mmHg-3.3 (-9.18, 2.68)2.9 (-1.18, 6.97)-6.2 (-13.26, 0.97)0.09
      Diastolic BP, mmHg-2.6 (-5.38, 0.19)2.8 (-0.24, 5.88)-5.4 (-9.50, -1.33)0.01
      hs-CRP, mg/L4.64 (-0.94, 10.23)0.81 (-0.56, 2.18)3.83 (-1.90, 9.57)0.19
      Plasma glucose, mmol/L0.04 (-0.68, 0.77)-0.06 (-0.65, 0.54)0.1 (-0.83, 1.03)0.83
      eGFR, mL/min/1.73 m21.40 (-0.81, 3.60)0.73 (-1.50, 2.95)0.67 (-2.42, 3.76)0.67
      Total cholesterol, mmol/L0.22 (-0.55, 0.98)-0.09 (-0.31, 0.14)0.3 (-0.49, 1.10)0.45
      HDL-cholesterol, mmol/L-0.10 (-0.18, -0.03)-0.02 (-0.09, 0.05)-0.09 (-0.19, 0.01)0.08
      LDL-cholesterol, mmol/L-0.10 (-0.31, 0.11)-0.05 (-0.22, 0.13)-0.05 (-0.32, 0.22)0.71
      Triglycerides, mmol/L-0.06 (-0.29, 0.17)-0.05 (-0.25, 0.14)-0.01(-0.31, 0.29)0.96
      Apolipoprotein B, g/L-0.09 (-0.18, -0.00)-0.06 (-0.13, 0.01)-0.03 (-0.14, 0.08)0.59
      Apolipoprotein A1, g/L0.02 (-0.07, 0.10)0.01 (-0.08, 0.09)0.01 (-0.11, 0.13)0.88
      Presented as mean (95% CI). BP = blood pressure. hs-CRP = high-sensitivity C-reactive protein. eGFR = estimated glomerular filtration rate. P-value results from two-sample t-tests.

      Arterial stiffness

      Arterial stiffness was measured at baseline and at end of study using the SphygmoCor® method. Compared with the CNI group, central diastolic pressure in patients of the belatacept group decreased by 6.55 mmHg (95%CI: 1.83, 11.27; p = 0.01) after one year of treatment. For central systolic pressures, the difference of 6.1 mmHg between study groups (95% CI: -0.11, 12.34; p = 0.05) was borderline significant. There were no differences between the treatment arms in central pulse pressure, pulse wave velocity and augmentation index (Table 5).
      Table 5Change from baseline in arterial stiffness variables.
      Risk factorBelatacept armCNI armDifferencep-value
      Augmentation Index, %-1.26 (-4.51, 1.99)1.04 (-2.41, 4.48)-2.30 (-6.96, 2.37)0.33
      Pulse Wave Velocity, cm/sec-0.44 (-1.02, 0.13)0.1 (-0.88, 1.08)-0.54 (-1.67, 0.58)0.34
      Central systolic pressure, mmHg-4.45 (-9.09, 0.18)1.65 (-2.63, 5.94)-6.1 (-12.33, 0.11)0.05
      Central diastolic pressure, mmHg-3.72 (-7.41, -0.02)2.83 (-0.17, 5.84)-6.55 (-11.24, -1.86)0.01
      Central pulse pressure, mmHg-0.60 (-4.03, 2.83)-0.37 (-3.51, 2.77)-0.23 (-4.81, 4.35)0.92
      Presented as mean (95% CI). P-value results from two-sample t-tests.

      Cardiovascular events and patient survival

      During the one-year study period, there were no cardiovascular events observed (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to congestive heart failure or angina pectoris, or coronary intervention) or deaths in the study population.

      Safety evaluation

      All patients in both study groups reported at least one AE during the duration of the study (Table 6). The majority of the events were of mild severity and considered unrelated to study drug. More patients in the belatacept-group (53.7% vs 21.6%) reported AEs that were considered possibly or probably related to the intervention. Three patients in the belatacept-group and one patient in the CNI continuation group reported AEs that led to withdrawal from the study. Serious Adverse Events (SAEs) were reported by 29.6% of the patients in the belatacept-group compared with 15.7% in the CNI group. Patients allocated to the belatacept-group had more infections (Table 7). There was 1 case of incident cancer (lung cancer), which occurred in the belatacept-group.
      Table 6Number and proportion of patients with adverse events
      Belatacept armCNI arm
      n%n%
      Any adverse event5410051100
      1 adverse event1018.52141.2
      >1 adverse events4481.53058.8
      Any possibly or probably intervention-related adverse events2953.71121.6
      Adverse events leading to withdrawal35.612.0
      Serious adverse events1629.6815.7
      - suspected acute rejection713.012.0
      - biopsy-proven acute rejection47.412.0
      - graft loss due to acute rejection11.90-
      - cancer11.90-
      Table 7Adverse events reported by ≥5% of patients in either treatment group
      EventBelatacept arm (n=54)CNI arm (n=51)
      Urinary tract infection19 (35%)4 (8%)
      Pyrexia17 (32%)1 (2%)
      Abdominal pain/discomfort10 (19%)1 (2%)
      Nasopharyngitis10 (19%)8 (16%)
      Respiratory tract infection8 (15%)5 (10%)
      Coughing8 (15%)1 (2%)
      Oedema5 (9%)3 (6%)
      Diarrhoea5 (9%)2 (4%)
      Anemia5 (9%)1 (2%)
      Fatigue4 (7%)1 (2%)
      Headache4 (7%)1 (2%)
      Dizziness4 (7%)0
      Arthralgia2 (4%)3 (6%)
      Gastroenteritis1 (2%)3 (6%)
      Nausea3 (6%)1 (2%)
      Herpes zoster3 (6%)1 (2%)
      Myalgia3 (6%)1 (2%)
      Aphthous ulcer3 (6%)0
      Given as incidence rates in number (percentage).
      During the study, 8 acute rejection episodes were suspected, and graft biopsies were obtained for further investigation. Acute rejection was confirmed in 4 of the 7 suspected cases in the belatacept-group, and in the single case in the CNI group. Three of the rejection episodes were considered severe (Banff grade IIA or higher): two in the belatacept-group and in the CNI-treated patient. One patient (belatacept) proved refractory despite anti-rejection treatment with methylprednisolone and T-cell depleting antibody. All other rejection episodes recovered upon treatment with corticosteroids or anti-thymocyte globulin as per local practices.

      DISCUSSION

      In this randomized study, where stable kidney transplant patients were converted from a CNI-based maintenance immunosuppressive regimen to belatacept, no difference in calculated 7-year risk of MACE or all-cause mortality could be demonstrated after 1 year of follow-up. We were unable to find a significant effect on any of the three modifiable cardiovascular risk factors which were used as input-variables in the risk calculator (serum LDL-cholesterol, diabetes-prevalence, and serum creatinine). The belatacept arm had significantly lower diastolic blood pressure, measured both centrally (SphygmoCor® method) and peripherally. We found a similar improvement for systolic pressure (Table 4), but this difference was not statistically significant (p = 0.09).
      Of the three modifiable risk factors in the calculator, we had expected a significant change in eGFR in the intervention arm. Our findings are in contrast to the BENEFIT studies, as well as other belatacept conversion studies reported in the literature
      • Vincenti F.
      • Rostaing L.
      • Grinyo J.
      • et al.
      Belatacept and Long-Term Outcomes in Kidney Transplantation.
      ,
      • Vanrenterghem Y.
      • Bresnahan B.
      • Campistol J.
      • et al.
      Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies).
      • Florman S.
      • Becker T.
      • Bresnahan B.
      • et al.
      Efficacy and Safety Outcomes of Extended Criteria Donor Kidneys by Subtype: Subgroup Analysis of BENEFIT-EXT at 7 Years After Transplant.
      . In those studies, there was a consistent improvement in graft function by converting to belatacept. One possible explanation for this was the predominant use of TAC by our study participants with relatively low trough levels (Table 1) at baseline. In the Symphony trial
      • Ekberg H.
      • Tedesco-Silva H.
      • Demirbas A.
      • et al.
      Reduced exposure to calcineurin inhibitors in renal transplantation.
      , the low-dose TAC group had an average trough-level of 6.7 ng/ml one year after transplantation and achieved an eGFR on average 5.7 ml/min/1.73m
      • Jardine A.G.
      • Gaston R.S.
      • Fellstrom B.C.
      • Holdaas H.
      Prevention of cardiovascular disease in adult recipients of kidney transplants.
      higher than the other 3 comparator groups. A belatacept conversion study by Grinyo et al.
      • Grinyó J.M.
      • Del Carmen Rial M.
      • Alberu J.
      • et al.
      Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.
      examined 173 patients with a mean time after transplantation to randomization of 19 months, baseline eGFR of 54 ml/min/1.73m
      • Jardine A.G.
      • Gaston R.S.
      • Fellstrom B.C.
      • Holdaas H.
      Prevention of cardiovascular disease in adult recipients of kidney transplants.
      , and a low immunologic risk profile, making the population reasonably comparable to ours. Belatacept patients in that study showed an average improvement in eGFR of 4.9 ml/m/1.73m
      • Jardine A.G.
      • Gaston R.S.
      • Fellstrom B.C.
      • Holdaas H.
      Prevention of cardiovascular disease in adult recipients of kidney transplants.
      compared to CNI-patients. At baseline, patients using TAC (56%) had an average trough level of 7.2 ng/ml, while patients on CsA (44%) had an average trough level of 160.2 ng/ml. In our study, the mean trough levels of TAC (5.7 ng/ml) and CsA (91 ng/ml, 4 patients only) at the time of randomization were lower compared to both these studies
      • Ekberg H.
      • Tedesco-Silva H.
      • Demirbas A.
      • et al.
      Reduced exposure to calcineurin inhibitors in renal transplantation.
      ,
      • Grinyó J.M.
      • Del Carmen Rial M.
      • Alberu J.
      • et al.
      Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.
      . The lower CNI trough levels may have already significantly decreased the nephrotoxic side-effects and explain why our belatacept patients only experienced a non-significant gain in eGFR of 0.7 ml/m/1.73m
      • Jardine A.G.
      • Gaston R.S.
      • Fellstrom B.C.
      • Holdaas H.
      Prevention of cardiovascular disease in adult recipients of kidney transplants.
      . However, this hypothesis is not supported by Budde et al. in a recent study that used a very similar design to ours
      • Budde K.
      • Prashar R.
      • Haller H.
      • et al.
      Conversion from Calcineurin Inhibitor to Belatacept-based Maintenance Immunosuppression in Renal Transplant Recipients: a Randomized Phase 3b Trial.
      . Their results showed an average TAC trough level of 6.27 mg/l and 5.82 mg/l respectively at baseline and after one year in the control arm. The average difference in eGFR between belatacept and TAC at that point was already 6.8 ml/min, contrary to our findings. Of note, patients in our study with BPAR had a decrease in eGFR of 2.7 ml/min, compared to a rise of 1.1 ml/min in the others. The low number of events precludes any meaningful interpretation of these data, and the general lack of improvement in eGFR cannot be explained hereby.
      The second element of the calculator is diabetes status. Multiple studies have corroborated the diabetogenicity of TAC in transplantation
      • Fan Y.
      • Xiao Y.B.
      • Weng Y.G.
      Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis.
      • Knoll G.A.
      • Bell R.C.
      Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials.
      • Penninga L.
      • Penninga E.I.
      • Moller C.H.
      • Iversen M.
      • Steinbruchel D.A.
      • Gluud C.
      Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients.
      . Furthermore, reversibility of beta cell dysfunction and of post-transplant diabetes mellitus after TAC-withdrawal has been established in both animal studies and in clinical experience
      • Dai C.
      • Walker J.T.
      • Shostak A.
      • et al.
      Tacrolimus- and sirolimus-induced human beta cell dysfunction is reversible and preventable.
      • de Graav G.N.
      • van der Zwan M.
      • Baan C.C.
      • Janssen J.
      • Hesselink D.A.
      Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms.
      • Terrec F.
      • Jouve T.
      • Naciri-Bennani H.
      • et al.
      Late Conversion From Calcineurin Inhibitors to Belatacept in Kidney-Transplant Recipients Has a Significant Beneficial Impact on Glycemic Parameters.
      • Ghisdal L.
      • Bouchta N.B.
      • Broeders N.
      • et al.
      Conversion from tacrolimus to cyclosporine A for new-onset diabetes after transplantation: a single-centre experience in renal transplanted patients and review of the literature.
      . Thus, we expected to improve glycemic metabolism in converting from TAC to belatacept. However, no participant in our study reversed diabetes mellitus or developed post-transplant diabetes mellitus in either study arm (Table 3). Also, triglycerides, serum ApoB, and serum ApoA1 did not improve (Table 4), which is of interest, since all three of these parameters are mentioned as risk factors for developing post-transplant diabetes mellitus
      • Malyala R.
      • Rapi L.
      • Nash M.M.
      • Prasad G.V.R.
      Serum Apolipoprotein B and A1 Concentrations Predict Late-Onset Posttransplant Diabetes Mellitus in Prevalent Adult Kidney Transplant Recipients.
      ,
      • Guzman G.E.
      • Victoria A.M.
      • Ramos I.
      • et al.
      Risk Factors Related to New-Onset Diabetes after Renal Transplantation in Patients of a High Complexity University Hospital in Colombia, 20 Years of Experience.
      .
      Expectations regarding the effect on lipid profile, the third element in the calculator, were limited. While CsA has been implicated in dyslipidemia
      • Mathis A.S.
      • Dave N.
      • Knipp G.T.
      • Friedman G.S.
      Drug-related dyslipidemia after renal transplantation.
      , TAC seems to be less detrimental to lipid status. In our study, 94% of the participants were on TAC before randomization. Ferguson et al.
      • Ferguson R.
      • Grinyo J.
      • Vincenti F.
      • et al.
      Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients.
      compared three steroid-avoiding regimens of immunosuppression: belatacept with MMF vs belatacept with sirolimus vs TAC with MMF. Both belatacept-arms had lower LDL (23.9 mg/ml and 25.0 mg/ml vs 34.0 mg/ml for TAC with MMF) after one year, but the difference was non-significant, possibly related to the limited sample-size of the study. Another observational study focusing on the metabolic effects of conversion from TAC to belatacept found improvement in GFR and acid-base status, but not in blood lipids
      • Schulte K.
      • Vollmer C.
      • Klasen V.
      • et al.
      Late conversion from tacrolimus to a belatacept-based immuno-suppression regime in kidney transplant recipients improves renal function, acid-base derangement and mineral-bone metabolism.
      . Our findings are in line with these reports, as we found no effect on LDL-cholesterol (Table 3).
      In trying to explain the lack of significant improvement of CV-risk, we need to consider another bias besides the low CNI trough levels. Patients were already treated with CNI for a median of 26 months since transplantation. Serious negative side effects of CNI-treatment could be less likely found in the control group, as patients suffering from these side effects could have been converted to alternative immunosuppression earlier on and thus not be eligible for this study. The only positive effect that we found for belatacept was a significant improvement in diastolic blood pressure, measured both centrally (SphygmoCor® method) and peripherally. For systolic pressure, a similar improvement was found (Table 4), but it was not statistically significant (p = 0.09), most likely due to the relatively small sample size of this study. Calcineurin inhibitors (CNI) are known as potent vasoconstrictors and contribute to post-transplant hypertension
      • Calo L.A.
      • Ravarotto V.
      • Simioni F.
      • et al.
      Pathophysiology of Post Transplant Hypertension in Kidney Transplant: Focus on Calcineurin Inhibitors Induced Oxidative Stress and Renal Sodium Retention and Implications with RhoA/Rho Kinase Pathway.
      . A previous study comparing belatacept and CsA on central aortic blood pressure and arterial stiffness after kidney transplantation has shown no differences in blood pressure, both centrally and peripherally, in the two groups
      • Seibert F.S.
      • Steltzer J.
      • Melilli E.
      • et al.
      Differential impact of belatacept and cyclosporine A on central aortic blood pressure and arterial stiffness after renal transplantation.
      . However, the study was also hampered by a low sample size and may have lacked the power to detect significant differences. Although not included in the calculator, blood pressure is of course an established risk factor for cardiovascular disease. Moreover, high blood pressure is strongly associated with risk of graft failure and finding an improvement in this parameter could still indicate an advantage for belatacept-treatment
      • Mangray M.
      • Vella J.P.
      Hypertension after kidney transplant.
      .
      Regarding safety, AEs occurred in both groups, but SAEs were reported almost twice as often in belatacept-treated patients (29.6% vs 15.7%), and these were more likely to discontinue their study treatment than patients treated with CNI (5.6% vs 2.0%). Rejection was seen more often in the belatacept-patients. Four episodes of biopsy-proven acute rejections occurred in the belatacept-group vs one single episode in the CNI-group (7.4% vs 2.0%). Three patients showed signs of vascular inflammation in the biopsy, corresponding to Banff grade II, two of which were in the belatacept-group. All three patients were treated according to local protocol with high-dose steroids and T-cell depleting antibodies, despite which one belatacept-patient suffered graft loss and re-initiated dialysis treatment. The other two recovered with anti-rejection treatment. The median number of days between transplantation and randomization was 225 in those on belatacept with biopsy-proven acute rejection, while no rejection was seen in any patient after 1 year after transplantation (mean 818 days after transplantation for those without biopsy-proven acute rejection). This trend of rejection after early conversion corroborates the findings by Budde et al., in which all belatacept-rejections was seen within 1 year of transplantation
      • Budde K.
      • Prashar R.
      • Haller H.
      • et al.
      Conversion from Calcineurin Inhibitor to Belatacept-based Maintenance Immunosuppression in Renal Transplant Recipients: a Randomized Phase 3b Trial.
      .
      The rate of rejection in this study is in line with earlier reports. For example, in the trial by Grinyo et al.
      • Grinyó J.M.
      • Del Carmen Rial M.
      • Alberu J.
      • et al.
      Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.
      , 7.1% of belatacept-patients experienced rejection versus none in the CNI-group. In another trial by Adams et al.
      • Adams A.B.
      • Goldstein J.
      • Garrett C.
      • et al.
      Belatacept Combined With Transient Calcineurin Inhibitor Therapy Prevents Rejection and Promotes Improved Long-Term Renal Allograft Function.
      , 1-year rejection rates were around 50% when belatacept was used right after transplantation, declining to 33% when TAC was tapered off 3-5 months after transplantation. When TAC was tapered after 11 months, the rejection rates between TAC- and belatacept-treated patients were similar, around 16%. Other reports have described varying (0-11%) rates of rejection, but these are data from non-randomized ‘rescue’-settings after even longer time post-transplantation and are therefore comparable with our results
      • Brakemeier S.
      • Kannenkeril D.
      • Dürr M.
      • et al.
      Experience with belatacept rescue therapy in kidney transplant recipients.
      ,
      • Gupta S.
      • Rosales I.
      • Wojciechowski D.
      Pilot Analysis of Late Conversion to Belatacept in Kidney Transplant Recipients for Biopsy-Proven Chronic Tacrolimus Toxicity.
      .
      Beside rejection, urinary tract infections, nasopharyngitis and other respiratory tract infections were more often seen in the belatacept arm (Table 7). The present study’s planned visits could have led to a bias in the reporting of uncomplicated infections, since a study visit was planned every month for belatacept-patients, instead of every 3 months for the CNI-continuation group.
      Not a single case of pneumocystis-jirovecii pneumonia, cytomegalovirus- (CMV), polyoma- or EBV-associated disease was seen in the belatacept-patients. Three cases of CMV-infection were seen in CNI-patients. Previous reports have been inconclusive on opportunistic infections in belatacept-treatment. The follow-up study to the first belatacept-conversion trial noted a slightly higher incidence of viral infection (11% vs 14%)
      • Grinyó J.M.
      • Del Carmen Rial M.
      • Alberu J.
      • et al.
      Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.
      . In a recent study by Bertrand e.a. 50 opportunistic infections were noted in 453 patients treated with belatacept (9.8%)
      • Bertrand D.
      • Terrec F.
      • Etienne I.
      • et al.
      Opportunistic Infections and Efficacy Following Conversion to Belatacept-Based Therapy after Kidney Transplantation: A French Multicenter Cohort.
      . In a multivariate analysis of that study, the authors concluded that patients with low GFR (<25 ml/min) and patients converted early after transplantation (within six months) were more likely to develop opportunistic infections.
      There was one case of lung cancer in the belatacept group in the present study. Previous studies have not indicated a higher risk of malignancy in belatacept beyond post-transplant-lymphoproliferative disorder
      • Vincenti F.
      • Rostaing L.
      • Grinyo J.
      • et al.
      Belatacept and Long-Term Outcomes in Kidney Transplantation.
      ,
      • Grinyó J.M.
      • Del Carmen Rial M.
      • Alberu J.
      • et al.
      Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial.
      .
      A major strength of the current study is the international multicenter approach, making it representative for European transplantation practice. However, this study also has important limitations which must be considered. The study duration of 1 year was most likely too short to reveal a significant difference in kidney function between the two study groups. We have overestimated the potential reduction in MACE and mortality for patients that use low-dose TAC instead of CsA. Another limitation was the heterogeneous time from transplantation to trial enrollment, and the small number of patients on CsA and the relatively large span of eGFR at baseline also contributed to the heterogeneity. Patients with severely diminished graft function were less likely to benefit from conversion.
      In conclusion, we have shown no effect on calculated CV risk or kidney function in this study comparing conversion to belatacept with continuation of CNI-based immunosuppression. We did show a significant difference in diastolic blood pressure. We re-confirmed the increased chance of rejection when converting to belatacept. After more than 10 years of clinical experience, the place of belatacept in kidney transplantation is still not fully established, but it may be an attractive option when patients suffer from significant side effects of CNI, like nephrotoxicity or post-transplant diabetes mellitus. However, it is hard to define a significant benefit of belatacept for patients who are doing well on low-dose TAC-based therapy without severe CNI-related side-effects. Further studies are needed to define the place of belatacept in kidney transplantation.

      Acknowledgements

      Smerud Medical Research International AS was responsible for administrative project management including monitoring, data management, statistical analyses and compilation of the full clinical study report. The authors wish to thank Andre Western as lead study monitor and Kristoffer Yunpeng Ding as lead statistician for their support. Study Steering committee: Prime principal investigator of each participating center; Hallvard Holdaas, Oslo; Alan Jardine, Glasgow; Bengt Fellström, Uppsala, chairman of SSC. Data and Safety Monitoring Board: Anders Hartmann, Oslo; Josep M Grinyo, Barcelona.
      Data Sharing: The data that support the findings of this study are available from the corresponding author upon reasonable request.
      Peer Review: Received April 2, 2022 as a submission to the expedited consideration track with 4 external peer reviews. Direct editorial input from the Statistical Editor and the Editor-in-Chief. Accepted in revised form September 24, 2022.

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