Association of a Change in Immunosuppressive Regimen with Hemodynamic and Inflammatory Markers of Cardiovascular Disease After Kidney Transplantation

Yong, Kenneth; Nguyen, Huong Van; Hii, Lawrence; Chan, Doris; Boudville, Neil; Messineo, Adriana M.; Lim, Ee Mun; Dogra, Gursharan; Lim, Wai H.

doi:10.1093/ajh/hpt017

Cited by 8 publications

(8 citation statements)

References 22 publications

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“…(25) In our study, at 2 years after transplant, HCC recurrence was seen only in the TAC arm, but numbers were low, thus not allowing a thorough between-group comparison. The mTOR inhibitors could also potentially lower the risk for cardiovascular events by reducing CNI-related hypertensive and diabetogenic effects (26) and possibly via direct cardioprotective effects, (27)(28)(29)(30) as suggested in a recent analysis of 1-year data from kidney transplantation. (31) In our smaller cohort, MACEs occurred only in the TAC group (3.8%).…”

Section: Discussionmentioning

confidence: 99%

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

et al. 2019

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The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR‐treated patients and 78 TAC‐treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR‐treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3‐12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2, respectively (P = 0.90) and adjusted mean change in eGFR from randomization was −8.0 versus −13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR‐treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC‐treated patients (P = 0.05). Treated biopsy‐proven acute rejection affected 4 EVR‐treated patients and 2 TAC patients during months 6‐24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR‐treated and TAC‐treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI‐free EVR‐based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.

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Section: Discussionmentioning

confidence: 99%

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

et al. 2019

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“…Similarly, CNI has been implicated in the promotion of endothelial dysfunction accounting for the impairment in glomerular filtration rate (GFR), cardiac allograft vasculopathy and perhaps contributes to long-term CV morbidity [Yong et al 2013; Nankivell et al 2004; Bloom and Reese, 2007]. In a prospective crossover trial, compared with renal recipients switched to SRL, after 5 months of TAC those maintained on the CNI had lower surrogate indices of CV disease that included pulse wave velocity and an aortic augmentation index that was adjusted for heart rate.…”

Section: Role Of Combined (Maintenance) Therapy In Adverse Metabolic mentioning

confidence: 99%

Metabolic consequences of modern immunosuppressive agents in solid organ transplantation

Bamgbola

2016

Therapeutic Advances in Endocrinology

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Among other factors, sophistication of immunosuppressive (IS) regimen accounts for the remarkable success attained in the short- and medium-term solid organ transplant (SOT) survival. The use of steroids, mycophenolate mofetil and calcineurin inhibitors (CNI) have led to annual renal graft survival rates exceeding 90% in the last six decades. On the other hand, attrition rates of the allograft beyond the first year have remained unchanged. In addition, there is a persistent high cardiovascular (CV) mortality rate among transplant recipients with functioning grafts. These shortcomings are in part due to the metabolic effects of steroids, CNI and sirolimus (SRL), all of which are implicated in hypertension, new onset diabetes after transplant (NODAT), and dyslipidemia. In a bid to reduce the required amount of harmful maintenance agents, T-cell-depleting antibodies are increasingly used for induction therapy. The downsides to their use are greater incidence of opportunistic viral infections and malignancy. On the other hand, inadequate immunosuppression causes recurrent rejection episodes and therefore early-onset chronic allograft dysfunction. In addition to the adverse metabolic effects of the steroid rescue needed in these settings, the generated proinflammatory milieu may promote accelerated atherosclerotic disorders, thus setting up a vicious cycle. The recent availability of newer agent, belatacept holds a promise in reducing the incidence of metabolic disorders and hopefully its long-term CV consequences. Although therapeutic drug monitoring as applied to CNI may be helpful, pharmacodynamic tools are needed to promote a customized selection of IS agents that offer the most benefit to an individual without jeopardizing the allograft survival.

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“…Clinical studies have consistently documented that TOR inhibitors sirolimus (rapamycin) and everolimus reduce cardiovascular risk in patients with coronary disease of native arteries, cardiac allograft vasculopathy, and kidney transplant recipients (Table 1). 29–47…”

Section: Protective Cardiovascular Effect Of Target Of Rapamycin Inhi...mentioning

confidence: 99%

“…Prospective clinical trials reveal a reduction of arterial stiffness in kidney transplant recipients converted from calcineurin inhibitors (cyclosporin or tacrolimus) to TOR inhibitors (sirolimus or everolimus) compared with recipients who continue receiving anticalcineurin drugs, independently of confounding factors, suggesting that an immunosuppressive regimen based on TOR inhibition reduces arterial stiffness. [42][43][44] Likewise, a randomized prospective clinical trial shows that arterial stiffness is lower in kidney transplant recipients treated with sirolimus since transplantation compared with cyclosporin. At follow-up, arterial stiffness and systolic blood pressure were lower in patients on sirolimus compared with those in patients on cyclosporin, independently of plasma lipid values.…”

Section: Beneficial Effect Of Tor Inhibition On Arterial Stiffnessmentioning

confidence: 99%

“…28 Collagen gel-based scaffolds lined with vascular smooth muscle cells may improve vascular tissue assembly in vitro. 16 There is compelling evidence from clinical studies that target of rapamycin (TOR) inhibitors (sirolimus and everolimus), [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] cilostazol (a drug that elevates intracellular cyclic adenosine monophosphate (cAMP) concentration), and microtubule-destabilizing agents (colchicine) [72][73][74][75][76][77][78][79][80][81][82] improve vascular disease and confer cardiovascular protection, although their indications in the clinical field remain to be established. The mechanisms by which these agents improve vascular function are not fully understood, but they may converge with the actin cytoskeleton and its putative impact on ECM synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular protection associated with cilostazol, colchicine and target of rapamycin inhibitors

Adeva‐Andany

Fernández‐Fernández

Carneiro-Freire

et al. 2022

Journal of Cardiovascular Pharmacology

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:An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

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Association of a Change in Immunosuppressive Regimen with Hemodynamic and Inflammatory Markers of Cardiovascular Disease After Kidney Transplantation

Abstract: Our study suggests from the elimination of CNI for PSI may lower AIx75 and IL-18, both surrogate markers of CVD, but adequately powered, randomized, controlled studies are required to establish the causal relationship between immunosuppressive agents and CVD risk.

Cited by 8 publications

References 22 publications

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years

Metabolic consequences of modern immunosuppressive agents in solid organ transplantation

Cardiovascular protection associated with cilostazol, colchicine and target of rapamycin inhibitors

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