From Duke University Medical Center
Duke researchers uncover clue to kidney damage after heart surgery NEW ORLEANS – Duke University Medical Center researchers have uncovered an intriguing clue why one of every 12 patients undergoing coronary artery bypass surgery suffers serious kidney impairment, and they believe their findings provide a target for new medications aimed at protecting kidneys.
The culprits, the researchers say, may be toxins that are released into the bloodstream by bacteria residing in the gastrointestinal tract in response to the surgery. These toxins can cause inflammation in tissues throughout the body, particularly the kidneys, where they appear to negatively impact the kidneys' ability to filter blood.
"We found that patients who had higher levels of antibodies circulating in their blood to neutralize or soak up these toxins had much better kidney function after surgery," said Duke anesthesiologist Dr. Mark Stafford-Smith. "With this knowledge, we can now come up with an intervention that either dampens the release of these toxins or increases the production of the antibodies, or both." Stafford-Smith presented the results of his team's study today (Oct. 16) during the annual scientific sessions of the American Society of Anesthesiologists.
More than 750,000 patients worldwide undergo bypass surgery every year, and researchers estimate that about 8 percent of those will suffer kidney damage after surgery. While most cases of kidney damage are transient, up to 2 percent of patients will require kidney dialysis. Additionally, 60 percent of those requiring dialysis will die before hospital discharge, Stafford-Smith said, highlighting the importance of kidney protection in these patients.
The toxins in question, called endotoxins, come from a class of bacteria known as gram-negative bacteria that reside in the gut. The researchers believe the endotoxins are released in response to the use of the heart-lung machine – which circulates the blood throughout the body while surgeons operate on a stopped heart – triggering a cascade of immunological events leading to systemic inflammation, Stafford-Smith explained.
The Duke investigators wanted to determine if the levels of specific antibodies – endotoxin core antibodies (IgM EndoCAb) – played a role in the kidney injuries. They already knew that low levels of these antibodies corresponded to worse overall outcomes after surgery, but no one had studied their effects on kidney function.
To test their hypothesis, the researchers measured the levels of the antibodies in the blood of 461 patients before surgery and then correlated these levels with post-surgical levels of creatinine, a byproduct of normal metabolism. Kidneys normally filter creatinine out of the blood and excrete it in the urine, so higher than normal levels in the blood indicate that the kidneys' ability to filter blood has been impaired. Patients were separated into two groups – 182 patients with high levels and 279 patients with low levels of antibodies in their blood.
"We found a statistically significant association between low levels of the IgM EndoCAb levels and increased levels of creatinine," Stafford-Smith said. "Those patients with more of the antibodies in their blood appeared to have a greater level of protection for their kidneys."
Specifically, the peak rise from baseline in creatinine levels for those with high antibody levels was 20.9 percent, while patients with low antibody levels saw peak creatinine levels rise 31.3 percent. Additionally, this increase was independent of other factors, such as age, gender and diabetes, Stafford-Smith said.
"None of the medications designed to protect the kidneys of surgery patients has been shown to be effective," said Stafford-Smith. "Since kidney function after surgery is an important determinant of outcome and quality of life, it is important to come up with ways to protect the kidneys. We now may have a target."
Such therapies could include drugs that modulate the immune response, or even a vaccine that could be given before a surgery to stimulate the production of IgM EndoCAbs, he added.
"Even patients with minor kidney impairment after surgery have higher rates of in-hospital complications, tend to remain in intensive care units longer and will be discharged from the hospital later," Stafford-Smith said. "Additionally, the likelihood of these patients being discharged to an extended care facility is up to three times higher than for patients without kidney impairment." The research was supported by Eisai, Inc., Teaneck, N.J., in collaboration with Duke's Department of Anesthesiology.
Last year, Stafford-Smith's team was the first to demonstrate a genetic link between heart surgery patients who suffer kidney damage and those who don't. They found that a gene variant (APOE-4), already implicated in the most common form of Alzheimer's disease, appears to offer protection to the kidney.
Members of Stafford-Smith's team are Duke colleagues Barbara Phillips-Bute, Dr. Brian McCreath, Dr. Madhav Swaminatham and Dr. Mark Newman.
Note to editors: Dr. Mark Stafford-Smith can be reached at (919) 681-5046 or Staff002@mc.duke.edu. A color photograph of Dr. Stafford-Smith is available at http://dukemednews.duke.edu/gallery/detail.php?id=342