Standard-dose Calcineurin Inhibitors Research Articles

Induction therapy with mesenchymal stromal cells in kidney transplantation: a meta-analysis

ObjectiveThe aim of this meta-analysis was to evaluate the therapeutic effects of mesenchymal stromal cells (MSCs) versus traditional regimens for induction therapy in kidney transplantation (KT), especially the safety of MSC infusion, practicability of MSCs as induction therapy agents, and posttransplant complications.MethodsPubMed, Embase, EBSCO, Ovid, and the Cochrane Library were searched for prospective clinical trials that compared MSCs with traditional regimens for induction therapy in KT.ResultsFour trials were included, including a total of 197 patients. The pooled results revealed that MSC therapy had a lower 1-year infection rate than did the traditional therapies (RR = 0.65, 95% CI: 0.46–0.9, P = 0.01). There were no significant differences between the two protocols regarding the 1-year acute rejection (AR) rate (RR = 0.77, 95% CI: 0.41–1.45, P = 0.42), 1-year graft survival rate (RR = 0.99, 95% CI: 0.95–1.03, P = 0.74), delayed graft function (DGF) rate (RR = 0.54, 95% CI: 0.21–1.38, P = 0.2) and renal graft function at 1 month (MD = −1.56, 95% CI: − 14.2–11.08, p = 0.81), 3 months (MD = 0.15, 95% CI: − 5.63–5.93, p = 0.96), 6 months (MD = − 1.95, 95% CI: − 9.87–5.97, p = 0.63), and 12 months (MD = − 1.13, 95% CI: − 7.16–4.89, p = 0.71) postsurgery. Subgroup analysis demonstrated that the 1-year AR rate, 1-year graft survival rate, DGF rate, and renal graft function at 12 months postsurgery did not significantly differ between the low-dose calcineurin inhibitor (CNI) group and the standard-dose CNI group, indicating the potential benefits of successful CNI sparing in combination with MSC treatment. Moreover, when MSCs were applied as an alternative therapy rather than an additional therapy or allogeneic MSCs were utilized instead of autologous MSCs, all of the outcomes mentioned above were comparable.ConclusionInduction therapy with MSCs is safe and has similar immune response modulation effects to those of traditional regimens in the short term in KT recipients. However, regarding the long-term effects, as suggested by the 1-year infection rate and the potential of CNI sparing, MSC therapy has significant advantages. However, these advantages should be further verified in more well-designed, multicenter randomized controlled trials (RCTs) with large sample sizes and long follow-up periods.

Mid-Term Effectiveness of Everolimus on Heart Transplant Recipients with Renal Dysfunction or Transplant Coronary Artery Atherosclerosis

Everolimus (EVL) can be utilized after heart reduce calcineurin inhibitor (CNI) associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection and cardiac allograft vasculopathy (TCAV). Since 2007, we have primarily considered converting from mycophenolate mofetil with standard-dose CNIs to EVL with low-dose CNIs for the following recipients: 1) recipients with impaired renal function; 2) those with increases in or an initially large maximal intimal thickness (MIT) on routine intravascular ultrasound (IVUS) examinations; 3) donor derived TCAV; and 4) those with MMF-related leukopenia. In the present study, mid-term safety and effectiveness of EVL on heart transplant recipients with renal dysfunction or TCAV. A single-center, retrospective cohort study was conducted including 116 adult heart transplant patients between 1999 and 2018. Sixty nine of 116 patients was started EVL and patients who was initiated EVL due to renal dysfunction (n=21) with longer than 1 year follow-up of serum creatine and TCAV (n=22) with longer than 3 years follow-up of annual MIT measurement by IVUS were enrolled in this study. The trough levels of EVL were evaluated at 1 week after initiation. Once target trough levels of EVL (6-8 ng/mL) were achieved, the CNI dose was reduced to obtain target trough levels. EVL efficacy on renal dysfunction and TCAV and safety were assessed. In 21 patients given EVL due to renal dysfunction, serum creatinine was significantly decreased from initiation of EVL to 1 year after initiation (1.44 +/- 0.32 vs 1.23 +/- 0.36 mg/dL; p=0.0004), but that did not significantly changed since then. In 22 patients given EVL due to TCAV, MIT was significantly decreased from initiation of EVL to 3 years after initiation (1.20 +/- 0.38 mm vs 1.00 +/- 0.40 mm, p<0.001), but that did not significantly changed since then. EVL with low-dose CNI might play a role in short-term improvement in renal function and TCAV in heart transplant patients. However, immunosuppressive regimen to furtherly improve renal function or TCAV mid-term after initiation of EVL should be investigated.

Brain metabolic alterations in patients with long-term calcineurin inhibitor therapy after liver transplantation.

Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism. To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation. Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function. Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209±0.012 vs 0.222±0.010; P<0.001) and a significant increase in PCr (0.344±0.026 vs 0.321±0.017; P<0.001) compared to controls. Myo-Inositol in the CNI free group (2.719±0.549 institutional unit [iu]) was significantly lower compared to controls (3.181±0.425 iu; P=0.02), patients on low-dose (3.130±0.513 iu; P<0.05) and standard-dose CNI therapy (3.207±0.632 iu; P<0.02). Glutamate and glutamine levels correlated negatively with cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status Total Scale: R=-0.362, P=0.029). Long-term CNI therapy after liver transplantation might be associated with alterations of brain metabolites.

Efficacy and safety of everolimus plus low-dose calcineurin inhibitor vs. mycophenolate mofetil plus standard-dose calcineurin inhibitor in renal transplant recipients: A systematic review and meta-analysis .

To seek an optimized immunotherapy which can preserve renal function while maintaining low acute rejection rates, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of everolimus (EVR) plus low-dose calcineurin inhibitor (CNI) vs. mycophenolate mofetil (MMF) plus standard-dose CNI regimen after kidney transplantation (KT). We searched for RCTs comparing the outcomes of EVR plus low-dose CNI and MMF plus standard-dose CNI regimen after KT and identified eligible RCTs according to strict inclusion and exclusion criteria. Two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Eleven RCTs with 850 renal transplant recipients were included. This meta-analysis showed that EVR plus low-dose CNI regimen was associated with comparable renal function (standardized mean difference (SMD) 0.16, 95% CI (-0.03, 0.35), p=0.09) and a similar rate of acute rejection (risk ratio (RR) 1.16, 95% CI (0.96, 1.42), p=0.13), graft loss (RR 0.89, 95% CI (0.63, 1.24), p=0.49) and mortality (RR 1.19, 95% CI (0.69, 2.08), p=0.53) compared to MMF plus standard-dose CNI regimen. In addition, EVR plus low-dose CNI regimen could reduce the rate of cytomegalovirus and infection, whereas a lower rate of other adverse events were noted in MMF plus standard-dose CNI regimen. EVR plus low-dose CNI regimen was similar in efficacy and safety to MMF plus standard-dose CNI regimen after KT. However, this should be confirmed by further studies. .

Sirolimus-Based Immunosuppressive Regimens in Renal Transplantation: A Systemic Review

Sirolimus (SRL)-based immunosuppressive regimens have been used for preventing rejection after kidney transplantation. This review analyzes their merits and demerits compared with other conventional regimes from the aspects of acute rejection rate, graft function, as well as patient/graft survival rates. In general, SRL is mostly recommended to be used as conversion therapy from calcineurin inhibitor (CNI) after kidney transplantation in most studies. Minimization or withdrawal of cyclosporine A (CsA) could also be considered when it was combined with SRL. SRL can replace mycophenolate mofetil (MMF), and the CNI dose should be reduced appropriately in this setting. Quadruple maintenance regimens containing SRL need future study to clarify their superiority. De novo use of low-dose CNI combined with SRL has no apparent merits and thus is not recommended. De novo use of standard-dose CNI combined with SRL followed by maintenance, de novo use of CNI-free regimens, as well as SRL use in delayed graft function (DGF) patients who spare antibody induction and postpone CNI administration should also be avoided. SRL supports steroids withdrawal after kidney transplantation, and SRL combined with tacrolimus is recommended in this setting. Loading dose is recommended when initiating SRL treatment and its trough blood level should be routinely monitored.

Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients

BackgroundWhether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression. MethodsWe retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2±2.3years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4±2.2years after HTx). The EVL group underwent three-dimensional intravascular ultrasound (3D-IVUS) analysis before and 1year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group. ResultsIVUS indices in the EVL group at 1year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (≥2years) also did not exhibit increased CAV development, while those in the MMF group did. ConclusionsConversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices.

Abstract 11167: Effects of Conversion to Everolimus With Low-Dose Calcineurin Inhibitors From Mycophenolate Mofetil on Cardiac Allograft Vasculopathy in Maintenance Heart Transplant Recipient: Serial Three-Dimensional Intravascular Ultrasound Analysis at 2 Years

Introduction: Everolimus (EVL) has been shown to reduce the severity of CAV in de novo heart transplant (HTx) recipients. However, there is still little knowledge about the effects of conversion from mycophenolate mofetil (MMF) to EVL with reducing calcineurin inhibitor (CNI) dose on cardiac allograft vasculopathy (CAV) in maintenance HTx recipients. To evaluate this hypothesis, we performed a retrospective study. Methods: We examined 63 consecutive HTx recipients who were investigated with three-dimensional intravascular ultrasound (3D-IVUS) analysis every year. 24 recipients were converted to EVL with low-dose CNI from MMF with standard-dose CNI (EVL group) while the others maintained on MMF with standard-dose CNI (MMF group). 3D-IVUS analyses in a year after conversions to EVL with low-dose CNI was compared with those just before the conversions in EVL group, while recent two 3D-IVUS analyses at one year interval were compared in the control group. Results: At the former analyses, plaque volume (PVI) and %plaque volume (%PVI, PVI/vessel volume percent) were significantly greater and lumen volume (LVI) was smaller in the EVL group in comparison with those in the MMF group. %PVI increased (10.37±7.53 versus 12.95±9.83, P=0.008) and LVI (10.57±2.63 versus 9.52±2.42 mm 3 /mm, P&lt;0.001) reduced significantly in the control group but not in the EVL group. The increase in %PVI during one year was suppressed and the decrease in LVI preserved in the EVL group compared with the control group (2.60±0.92 vs -0.66±1.14 %, p=0.031, -1.05±0.26 vs 0.05±0.19 mm 3 /mm, p=0.007, respectively). These effects were sustained at 2 years (p=0.042 and p=0.005). Conclusions: Compared with persistent MMF therapy, EVL conversion with low-dose CNI significantly reduce the severity of luminal narrowing in maintenance HTx recipients.

Alemtuzumab and Minimization Immunotherapy in Kidney Transplantation: Long-Term Results of Comparison With Rabbit Anti-Thymocyte Globulin and Standard Triple Maintenance Therapy

BackgroundEfforts to improve long-term patient and allograft survival have included use of induction therapies as well as steroid and/or calcineurin inhibitor (CNI) avoidance/minimization. MethodsThis is a retrospective review of kidney transplant recipients between September 2004 and July 2009. Immune minimization (group 1; n = 182) received alemtuzumab induction, low-dose CNI, and mycophenolic acid (MPA). Conventional immunosuppression (group 2; n = 232) received rabbit anti-thymocyte globulin, standard-dose CNI, MPA, and prednisone. ResultsBoth groups were followed up for same length of time (49.4 ± 21.7 months; P = .12). Patient survival was also similar (90% vs 94%; P = .14). Death-censored graft survival was inferior in group 1 compared with group 2 (86% vs 96%, respectively; P = .003). On multivariate analysis, group 1 was an independent risk factor for graft loss (aHR = 2.63; 95% confidence interval [CI], 1.32–5.26; P = .006). Biopsy-proven acute rejection occurred more in group 1, due to late rejections compared with group 2 (7% vs 2%; P < .01 respectively). Graft function was lower in group 1 compared with group 2 at 3 months (49.5 mL/mt vs 70.7 mL/mt, respectively; P < .001) to 48 months (48.6 mL/mt vs 69.4 mL/mt, respectively; P = .04). ConclusionMinimization of maintenance immunosuppression after alemtuzumab correlated with higher acute rejection and inferior graft survival compared with thymoglobulin and conventional triple immunotherapy.

Early use of renal-sparing agents in liver transplantation: A closer look

Renal dysfunction is a critical issue for liver transplant candidates and recipients. Acute nephrotoxicity and chronic nephrotoxicity, however, are the compromises for the potent immunosuppression provided by calcineurin inhibitors (CNIs). To maintain the graft and patient survival afforded by CNIs while minimizing renal dysfunction in liver transplant patients, the reduction, delay, or elimination of CNIs in immunosuppression regimens is being implemented more frequently by clinicians. The void left by standard-dose CNIs is being filled by nonnephrotoxic immunosuppressants such as mycophenolates and mammalian target of rapamycin inhibitors. The results of studies of renal-sparing regimens in liver transplant recipients have been inconsistent, and this may be explained upon a closer examination of several study-related factors, including the study design and the duration of follow-up.

Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients

Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case-control study on longitudinal growth over 2 years in steroid-free pediatric renal transplant recipients. Fourteen patients on a steroid-free maintenance immunosuppressive regimen consisting of low-dose everolimus (EVR) in conjunction with low-dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid-free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch-up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid-free pediatric patients on low-dose EVR and CsA is not different to that of a matched steroid-free control group on an immunosuppressive regimen with standard-dose CNI and MMF. Hence, low-dose EVR does not appear to negatively impact short-term growth in pediatric renal transplant recipients.

Induction Therapy With Autologous Mesenchymal Stem Cells in Living-Related Kidney Transplants

Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. clinicaltrials.gov Identifier: NCT00658073.

Everolimus: efficacy and safety in cardiac transplantation

Importance of the field: Prognosis after cardiac transplantation continues to improve with long-term outcomes limited by malignancy and coronary allograft vasculopathy (CAV). Everolimus may potentially reduce these late term complications, while maintaining the low cellular rejection rates seen with standard therapy.Areas covered in this review: Multiple studies have demonstrated the efficacy of everolimus in reducing acute rejection in heart transplant patients, progression and development of CAV, and the prevention and treatment of common malignancies, including skin cancer and Kaposi sarcoma. This review re-examines these studies with a focus on patient tolerability and safety.What the reader will gain: Tolerability and safety of everolimus remain a concern with pneumonitis, effusions, mouth ulcers, edema and impaired wound healing associated with morbidity and mortality. Studies have repeatedly demonstrated renal function deterioration with concomitant everolimus and a standard dose calcineurin inhibitor (CNI). This impact can be partly reduced with CNI dose reduction without an increase in the rate of rejection.Take home message: If future studies confirm reduced CAV and malignancy rates, everolimus will become an important agent in de novo and maintenance immunotherapy in cardiac transplantation. Patient centered immunotherapy is preferred to protocol-based immunotherapy as it allows tailoring of immune therapy to each individual patient's rejection risk and side profile.

Calcineurin Inhibitor Sparing in Renal Transplantation

Although calcineurin inhibitors (CNIs) are effective at preventing acute rejection, their long-term use is associated with nephrotoxicity that may compromise long-term renal allograft survival. Consequently, there is considerable interest in identifying immunosuppressive regimens that permit reduced exposure to CNIs while maintaining adequate immunosuppression. Introducing such strategies early after transplantation may mean that the development of CNI-associated nephrotoxicity could be minimized or prevented. Several CNI-sparing regimens have shown at least comparable efficacy with standard-dose CNI regimens. In particular, a regimen of mycophenolate mofetil (MMF), corticosteroids, interleukin-2 receptor antagonist induction, and low-dose tacrolimus from the time of transplantation provided superior renal function and a lower acute rejection rate than the same regimen but with low-dose cyclosporine or low-dose sirolimus, or standard-dose cyclosporine, MMF, and corticosteroids. The use of low-dose cyclosporine does not seem to eliminate nephrotoxicity in de novo renal transplant recipients. The early withdrawal of CNIs from MMF-based regimens generally improves renal function but has been associated with an increased risk of acute rejection, in particular when the levels of mycophenolic acid were not adjusted to maintain the same total level of immunosuppression. Research aiming to achieve the "best" balance of efficacy and toxicity of available immunosuppressive regimens continues.

Target of Rapamycin Inhibitors (Sirolimus and Everolimus) for Primary Immunosuppression of Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Trials

Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients. Databases (inception, June 2005) and conference proceedings (1996-2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values<1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74-1.44), but serum creatinine was lower (WMD, -18.31 micromol/L; 95% CI, -30.96 to -5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12-3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97-16.36; and anaemia: RR, 1.67; 95% CI, 1.27-2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71-0.99; RR, 0.49; 95% CI, 0.37-0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32-2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06-1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12-7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52-0.88), but calculated GFR was also reduced (WMD, -9.46 mL/min; 95% CI, -12.16 to -6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison. TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.