Red Blood Cell Pathology in Hemodialysis Patients By 2030, estimates predict that over 2 million people in the US will require hemodialysis as a result of end stage renal disease (ESRD). Patients receiving hemodialysis are at high risk for morbidity and mortality from cardiovascular complications. However, vascular access dysfunction, due to thrombosis and stenosis of the arteriovenous grafts, results in more hospitalizations than any other complication in this patient group. Underpinning the coagulation and cardiovascular events in these patients is the presence of profound inflammation and coagulation activation. However, the underlying cause of hyper-inflammation or -coagulation in patients on hemodialysis has yet to be determined. Healthy RBCs are designed to freely and permanently remain in, and sustain, the laminar flow of blood. These cells are strictly non-adhesive and maintain precise membrane asymmetry. If either of these physiological components is lost, the RBC converts into a proinflammatory, pro-coagulatory cell ? with detrimental and global effects on hemostasis. We have discovered that RBCs are adhesive and have lost membrane symmetry in patients on hemodialysis. Thus both of these physiological components of the RBC are disrupted in these patients.To date, no study has ever sought to examine the role of RBC pathology in inflammation and coagulation in ESRD patients on hemodialysis. We have found that RBCs from these patients are highly adhesive to pro-inflammatory cells in vasculature, and expose the pro-coagulatory lipid phosphatidylserine (PS) on their surface. We have further discovered that factors in the plasma of hemodialysis patients can induce these changes in the RBC. Thus, our data suggest that the RBC in these patients could be a major contributor to both inflammation and coagulation. What we do not know, however, are the mechanisms of RBC adhesion and pathological consequences of such adhesion. We do not know the fundamental changes in the RBC that occur during hemodialysis that allow PS to be exposed or activate such adhesion. Further, we do not know if any of these pathologies correlate to clinical outcome. This study seeks to answer those fundamental questions raised by our novel detection of RBC pathology in these patients. It promises, upon its completion, to open up entirely new avenues of therapy and understanding of inflammation and coagulation in ESRD patients on hemodialysis.
The mechanisms of inflammation and coagulation in patients with end stage renal disease on hemodialysis are poorly understood, but directly contribute to poor patient outcomes, including death. The role of the red blood cell in both inflammation and coagulation has never been investigated. We have discovered that red blood cells are adhesive in patients with end stage renal disease on hemodialysis, and have profound disruptions in membrane asymmetry. Both pathologies can contribute to both inflammation and coagulation in these patients. This proposal will identify the mechanisms and consequences of red blood cell adhesion in the patients, will determine the process through membrane asymmetry is disrupted and will begin to establish the clinical relevance of red blood cell pathology in patients with end stage renal disease on hemodialysis.
|Benson, Tyler W; Weintraub, Daniel S; Crowe, Matthew et al. (2018) Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding. Mol Cell Endocrinol 473:79-88|
|Brittain, Julia E; Anea, Ciprian; Desai, Payal et al. (2018) Effect of eptifibatide on inflammation during acute pain episodes in sickle cell disease. Am J Hematol 93:E99-E101|
|Benson, Tyler W; Weintraub, Neal L; Kim, Ha Won et al. (2018) A single high-fat meal provokes pathological erythrocyte remodeling and increases myeloperoxidase levels: implications for acute coronary syndrome. Lab Invest 98:1300-1310|
|Krishnamoorthy, Sriram; Pace, Betty; Gupta, Dipti et al. (2017) Dimethyl fumarate increases fetal hemoglobin, provides heme detoxification, and corrects anemia in sickle cell disease. JCI Insight 2:|
|Unruh, Dusten; Srinivasan, Ramprasad; Benson, Tyler et al. (2015) Red Blood Cell Dysfunction Induced by High-Fat Diet: Potential Implications for Obesity-Related Atherosclerosis. Circulation 132:1898-908|
|Amin, Chirag; Adam, Soheir; Mooberry, Micah J et al. (2015) Coagulation activation in sickle cell trait: an exploratory study. Br J Haematol 171:638-46|
|Brittain, Julia E (2014) Ironing out placenta growth factor. Blood 124:834-5|