Duke Researchers Uncover Genetic Link to Kidney Damage after Heart Surgery
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
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
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
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
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.