The Effect of Chronic Kidney Disease on Endothelial Function and Progenitor Cells
Kuczmarski, James Matthew
University of Delaware
Patients diagnosed with chronic kidney disease (CKD) are more likely to die of cardiovascular disease than progress to end stage renal disease. Evidence indicates that increased cardiovascular mortality in CKD patients may be related to compromised vascular integrity and ultimately endothelial dysfunction (ED) leading to poor tissue oxygen perfusion at not only renal but also cardiovascular tissues. Consequentially, progenitor-cell-based therapies have been suggested to preserve vascular continuity and induce vascularization, thereby preventing endothelial cell apoptosis, ED, and ultimately organ failure and cardiovascular events in CKD patients. The purpose of this investigation was to enumerate circulating progenitor cell (CPC) subpopulations of hematopoietic, endothelial, and myeloid lineage in CKD patients and compare them to apparently healthy controls. Additionally, a colony forming unit (CFU) assay was performed and endothelial-dependent dilation (EDD) was assessed using a non-invasive measurement of brachial artery reactivity known as flow-mediated dilation (FMD). We hypothesized that progenitor cell subpopulations would be reduced and CFUs as well as EDD would be impaired in the CKD subjects as compared to the healthy controls. Also, regression analysis was performed looking at the relationships between CPC subpopulations, CFUs, subject characteristics, and EDD measurements. Ten individuals with stages 3-5 CKD and ten apparently healthy controls were recruited, blood was drawn and brachial artery FMD was performed. CPCs were then quantified using the cell surface markers CD34, KDR, and CD45 with flow cytometry, and peripheral blood mononuclear cells isolated from the venousblood were cultured for the colony-forming assay. Renal function was significantly lower in the CKD patients as indicated by estimated glomerular filtration rate, elevated blood urea nitrogen, and increased serum creatinine levels. CKD patients also had significantly lower average percent changes in vessel diameter, and the hematopoietic progenitor subpopulations CD34+, CD34+/KDR+, CD34+/CD45-, and CD34+/KDR+/CD45- were reduced in this CKD sample. Furthermore, myeloid precursor populations CD45+ and CD45+/KDR+ were lower and colony forming ability was impaired in CKD patients with differences approaching statistical significance. Regression analysis indicated that the CPC subpopulations CD34+, CD34+/CD45-, and CD34+/KDR+/CD45-, in addition to EDD, were negatively associated with serum creatinine and blood urea nitrogen levels, whereas CD34+ and CD34+/KDR+/CD45- CPCs were also significantly positively correlated with percent change in vessel diameter. In conclusion, multiple subset populations of CPCs have been identified, shown to be reduced, and associated with EDD in the CKD population. Reductions in these progenitor cell subpopulations may be a potential mechanism by which vascular integrity is compromised and endothelial dysfunction results, increasing the risk of CVD and contributing to renal disease progression in CKD patients. Therefore, treatment strategies that target these specific subpopulations may be important in optimizing therapeutic effectiveness and ultimately improving renal and cardiovascular outcomes in this disease population.