The Effect of Chronic Kidney Disease on Endothelial Function and Progenitor Cells
Date
2010
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
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.