Kidney Patients’ HDL Loses Vasoprotective Function

HDL cholesterol from patients with chronic kidney disease (CKD) loses its protective effect on the cells lining blood vessels, the vascular endothelium. In patients with CKD, HDL appears to lose its anti-inflammatory effects and to become a proinflammatory substance, said Timo Speer, MD, of Saarland University Hospital in Hamburg, Germany.

The rate of cardiovascular (CV) events increases in patients with CKD long before they need dialysis. Dr. Speer called renal disease “a cardiovascular risk factor per se.” Epidemiologic studies have shown that in healthy people, the risk of coronary heart disease decreases 3 percent for every 1 percent increase in the normally protective HDL. Although HDL helps remove LDL, or bad, cholesterol from the circulation, it also has direct effects on the endothelium, including increased production of nitric oxide (which helps relax arteries) and antioxidant, anti-inflammatory, and antithrombotic effects. It also facilitates the healing of damaged endothelium.

CKD HDL limits endothelial nitric oxide production and increases adhesion molecules

Dr. Speer and colleagues isolated HDL from healthy control individuals and from patients with different stages of CKD to evaluate the effects of their HDL on endothelial function. The researchers first exposed aortic endothelial cells in vitro to the HDL that they had isolated, and they measured nitric oxide production. HDL from healthy volunteers increased production by about 10 percent, but HDL from patients with stage 5 CKD inhibited production by 40 percent compared with buffer-treated control individuals. The same levels of inhibition of nitric oxide production were seen when HDL from stage 2 or stage 3/4 patients was used. The more HDL that was added to the cultures, the greater were the effects: inhibition of nitric oxide production with HDL from patients with CKD or stimulation with HDL from healthy control individuals.

The researchers investigated the molecular mechanisms of the effects on nitric oxide production and found that CKD HDL increased phosphorylation of an inhibitory site and decreased phosphorylation of stimulatory sites on an enzyme, endothelial nitric oxide synthase. Healthy HDL promoted phosphorylation of stimulatory sites. Endothelial nitric oxide synthase is an enzyme that controls nitric oxide production, and phosphorylation of a site on the molecule promotes that site’s function—either inhibitory or stimulatory.

Healthy HDL decreased the production of vascular cell adhesion molecule-1 (VCAM-1) in the presence of the inflammatory mediator tumor necrosis factor- α (TNF- α), but CKD HDL was associated with a rise in VCAM-1 expression. VCAM-1 makes the endothelium sticky, promotes the adherence of certain kinds of blood cells, and may play a role in the development of atherosclerosis. Even without TNF- α “HDL from end stage renal disease patients becomes a proinflammatory particle,” Dr. Speer said.

HDL also affects healing of the endothelium after injury. Damaged endothelium may be dangerous because it loses its vascular protective functions and allows clots to form in the vessels. HDL from healthy volunteers reduced the apoptosis rate of endothelial cells, Dr. Speer said, “while HDL from dialysis patients had no effect.” Apoptosis is a natural process of programmed cell death, so a high rate of apoptosis limits the ability of the endothelium to regenerate.

Experimentally injured endothelium exposed to healthy HDL showed a rate of healing almost threefold higher than did control samples, but exposure to CKD HDL inhibited healing by about 20 percent compared with control samples.

October-November 2011 (Vol. 3, Number 10 & 11)