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Kidney Disease of Diabetes in the Pima Indians.

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"The Gila River Indian Community may be the smallest town in the United States with its own dialysis center," says Dr. Bill Knowler about this community of 11,000 people. Dr. Knowler and his colleagues at the NIH suspect that the Pima Indians share a gene or genes that make them more likely to develop the kidney disease of diabetes (KDDM) that frequently leads to kidney failure.

The researchers have found that Pima Indians have over 20 times the rate of new cases of kidney failure as the general U.S. population, and diabetes is the culprit over 90 percent of the time. Furthermore, kidney disease is the leading cause of death from disease among Pima Indians who have diabetes.

American Indians have the highest rates of diabetes in the world. About half of adult Pima Indians have diabetes, which they get at a relatively young age. On average, Pima Indians are a mere 36 years old when they get diabetes, compared with Caucasians, who get it at about age 60. The longer a person has diabetes, the greater the risk for developing complications, such as kidney disease. However, recent research shows that keeping blood sugar as close to normal as possible can slow or even prevent complications.

A woman performing a test in a laboratory.

Under normal conditions, the kidneys, nestled on each side of the body under the rib cage, maintain body fluid and salt balance and remove waste. They also help regulate blood pressure and release erythropoietin, a hormone that tells the bone marrow to make red blood cells.

The filtering units of the kidney, called glomeruli, are made up of clusters of tiny blood vessels. They act "like a screen that normally lets water and waste products filter through but holds back most of the protein," Dr. Knowler explains. "Early in the course of diabetes, we are seeing changes in the size of the holes of the screen, so that more protein escapes into the urine," he added. Called micro-albuminuria, this excess protein may be one of the first clues that kidney damage has begun.

When the kidney's filters are damaged, the remaining ones have to work harder to make up for the loss. As more of the filters are damaged, the kidneys lose their ability to compensate. When the kidneys decline to only 5 or 10 percent of their original capacity, a person is diagnosed with end-stage kidney disease.

Drs. William Knowler, Robert Hansen, and Venkat Narayan discussing research results.
Drs. William Knowler, Robert Hansen, and Venkat Narayan discuss research results.

"The real tragedy of kidney disease is that it leads to kidney failure, which means that a person must go on dialysis or have a kidney transplant," Dr. Knowler says.

But recent studies bring hope that the years of collaboration between NIH, other scientists and the Pima community is beginning to bear fruit.

For example, the NIH researchers now know that Pima Indians are more likely to get kidney disease of diabetes if they have high blood pressure, even before onset of diabetes; if they have microalbuminuria, or a family history of protein in the urine or kidney disease; or if they have high blood sugar, or diabetes serious enough to require drug or insulin treatment. If the impact of these risk factors, such as high blood pressure, could be reduced, the onset of kidney disease might be prevented or slowed.

Even with this important information, investigators still needed to know what was happening inside the kidney before they could design treatment studies, according to Dr. Robert Nelson, a researcher from The Cleveland Clinic Foundation who works with Dr. Knowler.

A patient getting a blood test.

Dr. Nelson explains that studies of patients with insulin-dependent, or Type I diabetes showed that the kidney filters blood faster and the blood moves faster within the kidney when diabetes sets in. It is the higher pressure that comes with those changes that may damage the sensitive filters and allow protein to leak into the urine.

Scientists thought that if the disease process worked the same in Pima Indians with Type II diabetes as in people with Type I diabetes, a special type of drug that reduces blood pressure within the kidney might help prevent or slow the kidney disease. Such a drug, an angiotensin-converting-enzyme (ACE) inhibitor, was recently approved by the Food and Drug Administration for the treatment of kidney disease of Type I diabetes.

Encouraged by this information, the Diabetic Renal Disease Study group, with Dr. Nelson directing patient care, set out to discover whether the kidney in Type II diabetes behaves as it does in Type I diabetes. After measuring kidney function in over 200 Pima Indians, with and without diabetes or kidney disease, the researchers found that the amount of blood filtered within the kidney does increase at the onset of Type II, as it does in Type I diabetes. A large European study of kidney function in people with Type II diabetes found the same thing.

Scientists conducting clinical studies in a laboratory.

After several years of studying how kidney disease of diabetes occurs, Dr. Nelson now believes there is enough evidence to conduct clinical studies to try to prevent its development or progression. A trial using an ACE inhibitor is now under way. Dr. Nelson says that although it seems slow in coming, the research is a "deliberate process" designed to get the best information possible in order to give the best care possible.

In the meantime, the best defense against kidney disease of diabetes-in any group of people-is to try to prevent diabetes from developing at all by maintaining healthy weight, exercising, and following a healthy diet. This is the goal of a new NIH Diabetes Prevention Program in which the Pimas and other American Indians are participating.

Once a person has diabetes, kidney disease might be prevented or slowed by controlling blood sugar levels and blood pressure, and by maintaining healthy weight.

Doctors and the Pima Indians continue to work together toward the day when the Gila River Indian Community will no longer need a dialysis center.
- Mary Harris

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