Of several cardiovascular manifestations in chronic kidney disease (CKD), thrombosis represents a potentially life threatening complication. CKD environment (uremia) is a profoundly thrombogenic. For example, next to medication noncompliance, CKD is both the second highest risk factor (increasing the risk for stent thrombosis by 6-10 folds) and an independent risk factor, which strongly suggests the presence of CKD-specific mediators. Despite its magnitude (more than 20 million people, 10% of US population with CKD) and adverse repercussions on the national public health system, mediators of uremic thrombosis have remained elusive, hampering the progress in the fields of predictive biomarkers. Furthermore, anti-thrombotic therapeutics in CKD also poses challenges. Antiplatelet and antithrombotic agents exhibit suboptimal efficacy in CKD patients, underscoring a need for a CKD-specific therapeutic target. Therefore, thrombosis in CKD is an area of high unmet clinical need both from pathogenic and therapeutic perspectives. CKD is characterized by retention of several solutes/metabolites called `uremic solutes/toxins'. Highly protein-bound nature of some of them precludes their effective clearance with dialysis. Thus, perturbing their intracellular signaling represents the most practical approach to abate the induced thrombogenicity. We were the first to identify the prothrombotic property of indolic solutes such as indoxyl sulfate (IS), which induce tissue factor (TF, a potent procoagulant) to enhance thrombosis. Our very recent work uncovered Aryl Hydrocarbon Receptor (AHR) as a key mediator of this regulation and supported IS-AHR-TF, a CKD- specific thrombosis axis. A novel panel of AHR blockers (AHRBs) showed anti-thrombotic activities. The present proposal examines this uremic thrombosis axis mechanistically and translationally leveraging animal models and samples from a large cohort of human patients.
Aim 1 performs a mechanistic deconvolution of TF regulation by AHR, Aim 2 examines the in vivo relevance of AHR-TF-thrombosis in animal models of CKD, and Aim 3 correlates the serum IS, IA levels, AHR and TF activities with post-angioplasty thrombosis in Thrombosis in Myocardial Infarction-II (TIMI)-II cohort. This will be first study to analyze the uremic metabolites and validate IS-AHR-TF-thrombosis axis in a large US cohort. The present study will also support IS as a potential biomarker and AHR as a therapeutic target for uremic thrombosis. This interdisciplinary application will be facilitated by expertise of Drs. Vipul Chitalia, PI; a nephrologist and a junio physician-scientist focused on thrombosis in CKD patients), Katya Ravid, in platelet and vascular biology (co-investigator), David Sherr (co-investigator), in AHR biology, and Janice Weinberg, expert in Biostatistics and analysis of clinical studies; and consultants - David Salant, an experienced investigator in CKD animal models, Elazer Edelman, an experienced investigator in stent thrombosis and Naomi Hamburg, a clinical epidemiologist and cardiologist experienced in various translational cardiovascular studies such as Framingham Heart Study.

Public Health Relevance

Patients with chronic kidney disease (CKD) suffer from several cardiovascular complications, of which thrombosis in blood vessels is particularly life threatening. CKD substantially increases the risk thrombosis, especially after vascular procedures. Despite its frequent occurrence and devastating complications, the mechanism governing this complication remained poorly defined. We recently identified the retained metabolites in the sera of patients with CKD that enhance thrombosis. This project investigates the role of these pro-thrombotic metabolites and signaling pathway activated by them and how it influences the pathogenesis of thrombosis after vascular procedures. While elucidating the underlying mechanism, this project will examine both a potential biomarker to identify the CKD patients at risk of thrombosis and a novel drug target for uremic thrombosis, both of which will improve the anti-thrombotic therapeutics in CKD patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL132325-01
Application #
9081851
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kindzelski, Andrei L
Project Start
2016-03-16
Project End
2020-02-28
Budget Start
2016-03-16
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$435,000
Indirect Cost
$185,000
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Kolachalama, Vijaya B; Shashar, Moshe; Alousi, Faisal et al. (2018) Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans. J Am Soc Nephrol 29:1063-1072
Abbonante, Vittorio; Chitalia, Vipul; Rosti, Vittorio et al. (2017) Upregulation of lysyl oxidase and adhesion to collagen of human megakaryocytes and platelets in primary myelofibrosis. Blood 130:829-831
Gordon, Craig E; Chitalia, Vipul C; Sloan, J Mark et al. (2017) Thrombotic Microangiopathy: A Multidisciplinary TeamĀ Approach. Am J Kidney Dis 70:715-721
Shashar, Moshe; Belghasem, Mostafa E; Matsuura, Shinobu et al. (2017) Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci Transl Med 9:
Woolf, N; Pearson, B E; Bondzie, P A et al. (2017) Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy. Oncogenesis 6:e378
Shivanna, Sowmya; Kolandaivelu, Kumaran; Shashar, Moshe et al. (2016) The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia. J Am Soc Nephrol 27:189-201
Chitalia, Vipul (2014) AHR: A Temple of Tolerance to Toxemia. Sci Transl Med 6:
Chitalia, Vipul (2014) A Tug of War in the Periphery. Sci Transl Med 6:
Chitalia, Vipul (2014) Muscles Protect the Kidneys. Sci Transl Med 6:
Chitalia, Vipul (2014) ?-Ketoglutarate-A New Currency of Longevity. Sci Transl Med 6:

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