Treatment with everolimus is associated with a procoagulant state

doi:10.1016/j.thromres.2013.07.004

Thrombosis Research

Volume 132, Issue 2, August 2013, Pages 307-311

https://doi.org/10.1016/j.thromres.2013.07.004 Get rights and content

Abstract

Introduction

Renal transplant recipients are at increased risk of venous thromboembolic events, which is in part caused by their treatment with maintenance immunosuppressive drugs. Because we observed an increased incidence of venous thromboembolic events in renal transplant recipients treated with the mTOR inhibitor (mTORi) everolimus, we aimed to identify prothrombotic mechanisms of this immunosuppressive drug.

Materials and Methods

In a single center study, nested in a multi-center randomized controlled trial, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients, receiving the mTORi everolimus (n = 16, mTOR group) and compared them to a similar patient group, receiving a calcineurin inhibitor and/or mycophenolate sodium (n = 20, non-mTOR group). All patients were at least 6 months following transplantation with a stable transplant function.

Results

The use of an mTORi was associated with significantly higher levels of von Willebrand factor, prothrombin fragment 1 + 2, thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 as compared to a non-mTORi based immunosuppressive regimen.

Conclusions

Treatment with an mTORi leads to increased endothelial activation, thrombin formation and impaired fibrinolysis in renal transplant recipients. This suggests an increased risk of thrombotic events in renal transplant recipients treated with mTOR inhibitors. A prospective study to establish the precise risk of thrombotic events in these patients is urgently needed.

Introduction

Chronic kidney disease (CKD) is associated with an increased risk of venous thromboembolism (VTE), especially in the presence of a nephrotic syndrome [1], [2], [3]. Also, the first years after kidney transplantation the risk of VTE remains high with an annual incidence of 5-9% [4], [5]. This can be explained by several factors. Renal transplantation does not completely restore renal function: many renal allograft recipients still suffer from CKD showing a mean estimated creatinine clearance (eGFR) of about 55 ml/minute at 2 years following renal transplantation [6]. Furthermore, renal transplant patients are at risk of developing proteinuria, caused by either recurrence of the original kidney disease or chronic allograft nephropathy in most cases.

Another risk factor for thromboembolic disease after renal transplantation is the maintenance immunosuppressive medication. Both steroids and calcineurin inhibitors have prothrombotic properties [7], [8]. Little is known about the possible prothrombotic side effects of the mTOR-inhibitors (mTORi) sirolimus and everolimus in allograft recipients. Like calcineurin-inhibitors (CNI), mTORi have been associated with thrombotic micro-angiopathy, but the underlying mechanism is uncertain [9], [10], [11], [12]. Reduction in (local) production of vascular endothelial growth factor (VEGF) may play a pathogenetic role [12]. Also a direct effect on genes encoding PAI-1 [13] and tissue factor (TF), has been observed [14].

In a recent multicenter randomized controlled trial (MECANO), studying early cyclosporine withdrawal after six months and comparing maintenance therapy with prednisolone/cyclosporine A (P/CsA) to prednisolone/mycophenolate sodium (P/MPS) or prednisolone/everolimus (P/EVL) [15], we noted a high incidence of VTE in the everolimus treated patients. This observation, and the above described effects on endothelial cells, raised our suspicion of a relationship between mTORi and the occurrence of thrombotic complications.

To investigate whether treatment with mTOR inhibition leads to a procoagulant state, we measured parameters of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients participating in the abovementioned trial. We compared recipients of the mTORi everolimus (EVL) to recipients of a CNI and/or MPS-containing drug regimen.

Section snippets

Patients

This study was conducted as part of a larger prospective, multicenter randomized trial (MECANO) studying the effects of withdrawal of cyclosporine A (CsA) from an immunosuppressive regimen containing an IL-2 antagonist (basiliximab), CsA, prednisolone (P) and mycophenolate sodium (MPS) early after transplantation. Three University Hospitals in the Netherlands participated in this trial from January 2005 until September 2009: the Academic Medical Center in Amsterdam (AMC), the Leiden University

Results

We studied 2 differently treated patient groups after renal transplantation (mTOR versus non-mTOR). The characteristics of the 36 patients are shown in Table 1. There were 16 patients in the mTOR group and 20 in the non-mTOR group. All patients in the mTOR group were on P/everolimus (EVL). Of the 20 patients in the non-mTOR group, 11 were treated with triple therapy i.e. prednisolone/cyclosporine/mycophenolate sodium (P/CsA/MPS), 4 were treated with P/CsA, 4 with P/MPS and one was treated with

Discussion

In this pilot study we aimed to explore the influence of the mTORi everolimus on variables of coagulation, anti-coagulation and fibrinolysis in renal transplant recipients. We here demonstrate that vWF, F1 + 2, PAI-1 and TAFI levels are higher in patients treated with an mTORi compared to those on a non-mTORi based immunosuppressive regimen, suggesting that treatment with mTORi (i.e. everolimus) leads to increased endothelial cell activation, thrombin formation and impaired fibrinolysis as

Conflict of Interest Statement

The MECANO study was sponsored by a grant of Novartis Pharma.

Acknowledgements

We greatly acknowledge G. Nieuwenhuizen for her excellent support in collecting the data. We thank W.F. Kopatz and M.A. Weijne for performing the analyses. We thank SiLa Yong for technical assistance. We thank Prof. dr. M.M. Levi and prof S. Middeldorp from the Academic Medical Center, Amsterdam, the Netherlands, for critical comments. There were no funding sources.

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Cited by (38)

An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients
2022, Transplantation Reviews
As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients.
Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.
Thromboprophylaxis after renal transplantation and patient risk stratification: The case of mTOR inhibitors
2020, Thrombosis Research
Tissue Factor and Risk of Complications After Kidney Transplantation
2020, Transplantation Proceedings
Tissue factor (TF) is a membrane component of many cells and a strong activator of blood coagulation. Damage to the cells induces an increase in its expression and concentration in blood plasma. The injury and breakdown of the cells is inseparably connected with the harvesting and preservation of the kidney.
The aim of the study was an analysis of TF in the renal vein after of restoration of circulation in the transplanted kidney. An additional goal was to investigate the impact of warm ischemia on TF.
The examined group included 61 kidney recipients. Blood was taken from the renal vein in the first minute during reperfusion. Simultaneously, blood from a peripheral vein was also drawn. Apart from tissue factor (TF), I also examined thrombin/antithrombin complexes and fragments 1+2 of prothrombin.
In blood from renal veins, I noticed higher level of TF, thrombin/antithrombin complexes and fragments 1+2 of prothrombin in comparison with blood from peripheral veins (P < .0048, P < .016, P < .046, respectively). The 29 recipients (47% of the total) with postoperative complications had much higher concentrations of TF than others (P < .019). TF showed a strong positive correlation with the time of warm ischemia (r = 0.53864, P < .05).
The donor kidney appeared to be one of the main sources of TF in the blood of recipients. Warm ischemia significantly increased its concentration in renal vein blood. This concentration of TF may be associated with damage to the kidney. TF significantly increased the risk of postoperative complications.
Absence of interaction between rivaroxaban, tacrolimus and everolimus in renal transplant recipients with deep vein thrombosis or atrial fibrillation
2020, Vascular Pharmacology
No data are available on rivaroxaban use in renal transplant recipients and on its surmised interaction with immunosuppressants. The aim was to investigate potential interactions between rivaroxaban and immunosuppressants in this setting. Renal transplant recipients with a stable renal function treated with rivaroxaban and tacrolimus with or without everolimus were investigated. All drugs and creatinine concentrations were determined daily for 2 weeks after the start of anticoagulation. Blood samples were drawn at 8.00 am and 3–4 h later for trough and peak concentrations, respectively. Bleeding and thrombotic events were recorded during a minimum follow-up of 6 months. In 8 renal transplant patients, rivaroxaban levels showed a predictable pharmacokinetic trend, both at C_trough (30–61 μg/L) and at C_peak (143–449 μg/L), with limited variability in the 25th–75th percentile range. Tacrolimus (C_trough 3–13 μg/L; C_peak 3–16 μg/L), everolimus (C_trough 3–11 μg/L; C_peak 5–17 μg/L) and creatinine concentrations were stable as well. Immunosuppressors variability before and after rivaroxaban were 30% and 30% for tacrolimus, 27% and 29% for everolimus, respectively, as well as 14% and 3% for creatinine. For rivaroxaban monitoring, the reference change value better performed in identifying significant variations of its concentration. No patient had bleeding or thrombotic events, worsening of renal graft function, and signs of immunosuppressants toxicity during a mean follow-up of 23 (9–28) months. In conclusion, rivaroxaban does not seem to interact with tacrolimus and everolimus in renal transplant recipients. Both anticoagulant and immunosuppressive effects seem warranted, without major bleeding complications and effect on the graft function.
Evidence-based practice: Guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients
2019, Transplantation Reviews
The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.
Thrombotic events with proliferation signal inhibitor‒based immunosuppression in cardiac transplantation
2019, Journal of Heart and Lung Transplantation
Citation Excerpt :
One theory is that higher serum levels of pro-coagulant factors are present in patients taking PSIs. A study in renal transplant recipients found higher levels of pro-coagulant factors such as von Willebrand factor, pro-thrombin fragments 1 and 2, thrombin-activatable fibrinolysis inhibitor, and plasminogen activator inhibitor-1 in patients treated with everolimus compared with those treated with a CNI and/or mycophenolate mofetil.21 In addition, it is not evident whether the increased thrombotic events were due to the drug or to underlying comorbid conditions, such as renal dysfunction or malignancy, both known risk factors for VTE.
Some literature exists potentially linking proliferation signal inhibitors (PSIs) to venous thromboembolism (VTE). We sought to determine the impact of PSIs on development of VTE in heart transplant (HT) patients while controlling for other risk factors.
The incidence and predisposing factors of VTE were analyzed in this retrospective review of patients >18 years who underwent HT January 2000 to October 2016. Re-transplants, multiorgan transplants, or patients that expired within 30 days post-HT were excluded. VTE incidence rates are reported as number of events per 100 person-years. Cox proportional hazards models were used to assess the relationship between PSI exposure (time-varying covariate) and VTE.
Of 561 HT recipients, 112 received PSIs, started a median of 1.5 years post-HT. There were 102 total VTE events: 78 in PSI-naive patients during 2,547 patient-years (3.0 events per 100 person-years) vs 24 in PSI-exposed patients during 544 patient-years (4.4 events per 100 person-years). Cox proportional hazards models with PSI exposure as a time-varying covariate indicated the increased risk was statistically significant (unadjusted hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.31 to 3.49, p = 0.002). A VTE history was significantly associated with increased risk of VTE post-HT (HR 1.58, 95% CI 1.07 to 2.35, p = 0.022); however, the risk remained significant when adjusting for potential confounders, including previous VTE (HR 2.0, 95% CI 1.18 to 3.38, p = 0.010).
Exposure to PSIs is associated with a significant increase in risk for VTE even when controlling for other risk factors. When considering the use of PSI-based immunosuppression after HT, the risk of VTE over time should be weighed against the potential benefit.

View all citing articles on Scopus

^☆: Preliminary results of this study were presented orally at the International Congress of Transplantation (ICT) in Vancouver, August 2010.

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Regular ArticleTreatment with everolimus is associated with a procoagulant state☆

Abstract

Introduction

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conflict of Interest Statement

Acknowledgements

Kidney Int

J Thromb Haemost

Am J Kidney Dis

Am J Transplant

Am J Transplant

Transplant Proc

Transplant Proc

Blood

Am J Transplant

Trends Immunol

Blood

Am J Transplant

J Heart Lung Transplant

Ann Thorac Surg

Lancet

Chronic kidney disease increases risk for venous thromboembolism

J Am Soc Nephrol

Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms

Curr Opin Pulm Med

Venous thromboembolic complications after kidney and kidney-pancreas transplantation: a multivariate analysis

Transplantation

No difference in degree of interstitial Sirius red-stained area in serial biopsies from area under concentration-over-time curves-guided cyclosporine versus tacrolimus-treated renal transplant recipients at one year

J Am Soc Nephrol

Regular Article
Treatment with everolimus is associated with a procoagulant state☆