Genetic paradox: Gene implicated in Alzheimer's disease appears to protect kidneys of heart surgery patients

July 26, 2000

DURHAM, N.C. -- While the use of bypass surgery over the past 30 years has saved millions of patients with clogged coronary arteries, physicians have noticed a disturbing, and so far unsolved, trend -- up to 8 percent of these heart patients will suffer impairment of kidney function after surgery.

A study by Duke University Medical Center researchers offers intriguing clues to this phenomenon by finding a possible genetic link determining which heart patients are more likely to suffer kidney damage. This is the first time a genetic link has been made to kidney injury after surgery. The research team, led by Duke anesthesiologist Dr. Mark Stafford-Smith, found that a gene variant already implicated in the most common form of Alzheimer's disease appears to offer protection to the kidneys when compared to patients with the two other variants of the gene.

Ironically, a study by Duke investigators three years ago found that patients with this same E-4 variant of the apolipoprotein (APO) gene tended to suffer cognitive declines after bypass surgery at a higher rate than those patients without the E-4 variant However, E-4 appears to protect kidneys as well.

"These results are doubly intriguing in that the same genetic variant that appears to have negative effects on the brain appears to be linked to significant protection for the kidneys," Stafford-Smith said. "While we don't understand the reasons for this, it does suggest that the role of APOE-4 in heart surgery patients is much more complex than we previously thought."

The results of Stafford-Smith's study were published Friday (July 28) in the August edition of the journal Anesthesiology. The research was supported by grants from the National Institutes of Health and the American Heart Association.

Although this new genetic insight does not offer direct clinical applications at this point, Stafford-Smith said that the APOE-4 status of a potential heart patient should be taken into consideration by patients and surgeons when contemplating surgery, given the apparent higher risks for subsequent kidney complications and their long-term impacts on the quality of life.

"Since we have nothing available at the moment to stop the damage from occurring, the best tool we have is prevention," Stafford-Smith said. "APOE status can be an accurate predictor of how a patient's kidneys will respond to the surgery."

Each year, about 800,000 patients worldwide undergo bypass surgery, and researchers estimate that about 8 percent of those will suffer kidney damage after surgery. Most cases of such injury are transient, but up to 1 percent of all heart surgery patients will require kidney dialysis. "Even patients with minor kidney impairment after surgery will have higher rates of in-hospital complications, and will 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."

In the Duke study, researchers prospectively followed 564 randomly selected patients who received bypass surgery at Duke between 1989 to 1999, and compared the kidney function before and after surgery of patients with the three variants of the APOE gene: E-2, E-3 and E-4. Everyone has one of those three variants in his or her genetic makeup. E-3 is the most common.

To determine kidney function, researchers measure blood 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. The researchers found that the levels of creatinine in patients with the E-2 and E-3 variants were higher than those with the E-4 variant, Stafford-Smith explained. The differences were statistically significant.

Specifically, patients with the E-2 variant saw their creatinine levels increase from 1.04 mg/dl (milligrams per deciliter) before surgery to 1.34 mg/dl after surgery, while patients with the E-3 variant rose from 1.05 mg/dl to 1.27 mg/dl. As a comparison, those with the E-4 variant rose from 1.03 mg/dl to 1.19 mg/dl. Patients with diabetes saw similar increases: E-2 rose from 1.01 mg/dl to 1.30 mg/dl, E-3 rose from 1.04 mg/dl to 1.40 mg/dl, and E-4 rose from 1.02 mg/dl to 1.23 mg/dl.

"The genetic influence appears to be clinically significant," Stafford-Smith said. "After an analysis of all the variables, we determined that the genetic influence was greater than the combined influences of diabetes and high blood pressure."

Stafford-Smith said researchers do not know why kidney injury occurs during surgery, though there are several possible culprits, including the altered blood flow as a result of being placed on a heart-lung machine during surgery or the possibility that during the procedure, tiny bits of plaque along the walls of blood vessels become dislodged, travel to the kidneys and block the tiny blood vessels. Drugs used during the procedure may also contribute to the phenomenon, he added.

Researchers have known that not only is the E-4 variant linked to Alzheimer's disease, but that it is also a risk factor for developing heart disease. APOE, which is located on the surface of circulating fat particles, normally binds to liver cells, helping them clear cholesterol from the blood. However, the E-4 variant is unable to function properly, leading to a build-up of "bad" LDL cholesterol, which in turn can lead to atherosclerosis, a disease process that can create plaques in blood vessels that can lead to a heart attack or stroke.

In 1993, Duke neurologists and genetic researchers presented a novel view of Alzheimer's disease when they demonstrated that the E-4 variant was a risk factor predisposing people to developing the disease. Those with the E-4 variant tended to get the disease at an earlier age.
Members of Stafford-Smith's team are, all from Duke: Dr. Sophia Chew, Dr. Mark Newman, William White, Dr. Peter Conlon, Dr. Ann Saunders, Dr. Warren Strittmatter, Dr. Kevin Landolfo, and Dr. Hilary Grocott.

Duke University Medical Center

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