Antithrombotic Therapy in Patients With Chronic  Kidney Disease

Capodanno, Davide; Angiolillo, Dominick J.

doi:10.1161/circulationaha.111.084996

Cited by 130 publications

(113 citation statements)

References 117 publications

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“…Historically, managing thrombosis in CKD patients has proven challenging. Pharmacokinetics limits agent selection 30 whereas retained products augment bleeding risk. 31 Conventional antithrombotics have consistently proven inadequate in CKD in numerous clinical scenarios.…”

Section: Discussionmentioning

confidence: 99%

“…Targeting AHR directly with AHR antagonists is expected to have fewer off-target effects and may even offer unique advantages with respect to bleeding. While most antithrombotics target blood-borne coagulation components systemically, thus increasing bleeding risks in uremic patients, 30,31 AHR antagonists may preferentially act at sites of local vascular damage (i.e., the vSMC compartment), despite systemic administration.…”

Section: Discussionmentioning

confidence: 99%

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The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Shivanna

Kolandaivelu

Shashar

et al. 2016

Journal of the American Society of Nephrology

146

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Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Shivanna

Kolandaivelu

Shashar

et al. 2016

Journal of the American Society of Nephrology

146

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“…33 Currently, there is no definitive measure to estimate the risk of bleeding in patients with CKD in whom anticoagulant therapy is contemplated. Bleeding risk scores, such as HAS-BLED and HEMORR(2)HAGES, have poor predictive power and limited clinical utility.…”

Section: Discussionmentioning

confidence: 99%

Comparisons between Novel Oral Anticoagulants and Vitamin K Antagonists in Patients with CKD

Harel¹,

Sholzberg

Shah³

et al. 2014

Journal of the American Society of Nephrology

101

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Novel oral anticoagulants (NOACs) (rivaroxaban, dabigatran, apixaban) have been approved by international regulatory agencies to treat atrial fibrillation and venous thromboembolism in patients with kidney dysfunction. However, altered metabolism of these drugs in the setting of impaired kidney function may subject patients with CKD to alterations in their efficacy and a higher risk of bleeding. This article examined the efficacy and safety of the NOACs versus vitamin K antagonists (VKAs) for atrial fibrillation and venous thromboembolism in patients with CKD. A systematic review and meta-analyses of randomized controlled trials were conducted to estimate relative risk (RR) with 95% confidence interval (95% CIs) using a random-effects model. MEDLINE, Embase, and the Cochrane Library were searched to identify articles published up to March 2013. We selected published randomized controlled trials of NOACs compared with VKAs of at least 4 weeks' duration that enrolled patients with CKD (defined as creatinine clearance of 30-50 ml/min) and reported data on comparative efficacy and bleeding events. Eight randomized controlled trials were eligible. There was no significant difference in the primary efficacy outcomes of stroke and systemic thromboembolism (four trials, 9693 participants; RR, 0.64 [95% CI, 0.39 to 1.04]) and recurrent thromboembolism or thromboembolism-related death (four trials, 891 participants; RR, 0.97 [95% CI, 0.43 to 2.15]) with NOACs versus VKAs. The risk of major bleeding or the combined endpoint of major bleeding or clinically relevant nonmajor bleeding (primary safety outcome) (eight trials, 10,616 participants; RR 0.89 [95% CI, 0.68 to 1.16]) was similar between the groups. The use of NOACs in select patients with CKD demonstrates efficacy and safety similar to those with VKAs. Proactive postmarketing surveillance and further studies are pivotal to further define the rational use of these agents.

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“…Biorąc pod uwagę głównie nerkową eliminację dabigatranu, co prowadzi do akumulacji leku i potencjalnie wiąże się z większą liczbą powikłań krwotocznych, to teoretycznie pacjenci z CKD mogliby odnosić korzyść z zastosowania leku w mniejszej dawce. Należy unikać jednoczesnego podawania dabigatranu i inhibitorów GP IIb/IIIa u pacjentów z CKD w 4. stadium [451]. U chorych z eGFR < 50 ml/min/1,75 m 2 jest wymagana modyfikacja dawkowania riwaroksabanu z 20 do 15 mg raz/dobę, a leku nie zaleca się pacjentom z CKD w 5. stadium [452].…”

Section: Dostosowanie Dawek Leków Przeciwzakrzepowychunclassified

2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

Roffi¹,

Patrono²,

Collet³

et al. 2015

Kardiol Pol

207

165

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Antithrombotic Therapy in Patients With Chronic Kidney Disease

Cited by 130 publications

References 117 publications

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Comparisons between Novel Oral Anticoagulants and Vitamin K Antagonists in Patients with CKD

2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

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