Mar. 18, 2005 DURHAM, N.C. – Specific variants of genes involved in inflammation and blood vessel constriction are strongly associated with kidney damage in patients undergoing major heart surgery, researchers at Duke University Medical Center have found.
While renal dysfunction after heart surgery is a common occurrence, until now researchers have been unable to predict with any certainty which patients – based on their personal and medical characteristics – are at the highest risk. The current analysis showed that patients with the particular genetic variants, or polymorphisms, have a collective two- to four-fold greater likelihood of suffering renal dysfunction after heart surgery.
This is important, the researchers said, since one out of every 12 patients who undergo heart surgery suffers serious kidney impairment. While most cases of this kidney injury are transient, up to two percent of patients will require kidney dialysis, with 60 percent of those patients dying before hospital discharge. Since more than 750,000 patients worldwide undergo heart surgery every year, the magnitude of the problem is large, the researchers said.
The results of the Duke analysis were published in the March, 2005 issue of the American Journal of Kidney Disease. The research was supported by the National Institutes of Health and the American Heart Association.
"If the results of our study are borne out in other populations, they should not only be useful for physicians as they counsel their patients who are undergoing heart surgery, but may also help physicians as they decide between medical or surgical treatments, based on a patient's unique characteristics and genetic make-up," said lead researcher Mark Stafford-Smith, M.D., Duke cardiothoracic anesthesiologist. "This new genetic information may also help facilitate individually tailored medical therapy designed to reduce renal injury and its subsequent medical problems."
For the study, the researchers followed 1,671 patients who underwent heart surgery at Duke University Hospital. Prior to surgery, the researchers performed genetic analysis of blood samples paying particular attention to 12 candidate polymorphisms on seven genes. These target genes were chosen because earlier studies suggested that they may play a role in kidney injury.
To determine kidney damage, the researchers measured the levels of creatinine, a normal byproduct of metabolism, in the blood after surgery. Higher-than-normal blood levels of creatinine indicate an impairment in the kidney's ability to filter, because kidneys normally filter creatinine out of the blood and excrete it in the urine. Typically, creatinine levels peak two days after surgery and return to normal by day five.
The researchers then correlated the individual polymorphisms with the peak levels of creatinine measured after surgery. Since race has already been determined to be an important independent predictor of kidney damage after surgery, the researchers performed separate analyses of Caucasians and African-Americans.
In Caucasians, the researchers found that patients having two polymorphisms involved in the inflammatory response – angiotensinogen 842C and interleukin 6-572C – had on average an 121 percent increase in creatinine, which is equivalent to a 55 percent reduction in the kidney's ability to filter waste. This rate was four times higher than the study population as a whole.
"This combination of the polymorphisms, which is present in about 6 percent of all Caucasians, is related to the effects which are seen in the kidneys - which we speculate are due to an amplified immune system inflammatory response to the surgery," Stafford-Smith said.
While the very act of surgery stimulates an immune system response, it has also been shown to cause blood vessel constriction, especially in the kidneys, Stafford-Smith continued. During these periods of constriction, the kidney's supply of oxygen and nutrients can be restricted.
It is in this vasoconstriction phenomenon where it appears that different polymorphisms may explain the increased kidney damage seen in African–Americans, who if they possess two polymorphisms involved in vascular responsiveness – endothelial nitric oxide synthase 849T and angiotensin converting enzyme deletion allele – had a 162.5 percent increase in creatinine in the blood. This translates into a 60 percent reduction in the kidney's filtering ability, a rate more than twice as high as the study population as a whole.
"If this vulnerability is borne out in larger clinical trials, this would be a finding of great clinical significance," Stafford-Smith said. "The polymorphisms of these genes, since they are vital to controlling blood flow in the kidney, may contribute not only to the initial insult during low blood flow, but also throughout the recovery phase."
Some other polymorphisms also examined by the researchers showed smaller abilities to predict renal dysfunction after surgery. While these associations were weaker, Stafford-Smith said that the other polymorphisms, when combined with other factors, could still be relevant in predicting patients at risk.
Stafford-Smith added that there are likely other polymorphisms – whether expressed individually or in combination with others – that are involved in the kidney damage. Further studies are needed to confirm these findings in other populations, and to identify additional genetic factors, he added.
Other members of the team, all from Duke, are: Mihai Podgoreanu, M.D., Madhav Swaminatham, M.D., Barbara Phillips-Bute, Ph.D., Joseph Mathew, M.D., Elizabeth Hauser, Ph.D., Michelle Winn, M.D., Carmelo Milano, M.D., Dahlia Nielsen, Ph.D., Mike Smith, Richard Morris, Ph.D., Mark Newman, M.D., and Debra Schwinn, M.D. All are members of the Perioperative Genetics and Safety Outcomes Study (PEGASUS) team.
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