Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Clinical and Translational Science

First Advisor

Mary Cushman

Abstract

Chronic kidney disease (CKD) affects more than 30 million adults in the U.S. and is strongly associated with cardiovascular events and mortality. Venous thromboembolism (VTE) is the third leading vascular disease, affects up to 900,000 Americans each year and contributes to as many as 100,000 deaths annually. The relationship of CKD and VTE has been described in patients receiving dialysis, kidney transplants recipients and in nephrotic syndrome, however, data supporting the association of VTE in mild to moderate CKD is conflicted. The overall goal of this research was to study the association of CKD and VTE and to understand the mechanisms of this association. To accomplish this goal we studied participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a nationally representative cohort of 30,239 blacks and whites in the U.S..

The first chapter provides a review of the state-of-the science on CKD and VTE and potential mechanisms for this association. We focus on factor VIII as a potential mediator of VTE risk in CKD by reviewing the biochemistry and epidemiology linking factor VIII and CKD.

In Chapter 2, we use a cohort study design and a competing risk analysis to determine the risk of VTE with albuminuria (ACR) and with various equations for estimated glomerular filtration rate (eGFR). There was no association of ACR and VTE and the risk of VTE was similar among eGFR equations. Compared to a normal eGFR (>90 ml/min/1.73m2), eGFR < 45 ml/min/1.73m2 was associated with a two-fold risk of VTE. The association of eGFR and unprovoked VTE was similar to the association with provoked VTE. The population attributable fraction of CKD (eGFR<60 ml/min/1.73m2) was modest at 5%.

In Chapter 3, we utilize a case-cohort study to determine if biomarkers of inflammation (C-reactive protein) and procoagulation (Factor VIII and D-dimer) attenuate the risk of VTE in CKD. These biomarkers were higher in lower kidney function and were also strongly associated with VTE. Adjustment for factor VIII fully attenuated the risk of VTE in CKD, thus factor VIII is a potential mediator of the association of CKD and VTE. We assessed whether lifestyle factors and medications mitigate the risk of VTE in those with and without CKD. Exercise frequency and use of statins were associated with reduced risk of VTE in the presence and absence of CKD, but normal BMI was associated with reduced VTE risk only in those without CKD.

We conclude that CKD is a risk factor for VTE, and findings shed light on the mechanisms of this association. Interventions that might lower VTE risk in CKD patients include exercise and statin therapy, but not weight loss. Factor VIII is a potential mediator of VTE in CKD and deserves further study. We suggest several avenues for future research to explore the relationship of Factor VIII and CKD.

Language

en

Number of Pages

132 p.

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