Keys to Kidney Disease
Making early intervention possible could yield dramatic results
Researcher: Robert Toto, MD
Occupation: Mary M. Conroy Professorship in Kidney Disease, University of Texas Southwestern Medical Center at Dallas
Research Funding: ADA Clinical/Translational Research Award
The kidneys are designed to keep the blood clean. They contain millions of tiny blood vessels, each perforated with holes small enough to retain blood cells but big enough to let waste products through, like a fine-mesh sieve. This is how the junk generated as the body turns protein into fuel gets passed into the urine, while useful proteins and blood cells stay in circulation.
Diabetes can make the kidneys' job particularly hard. High blood glucose increases the amount of blood that flows through the kidneys and needs to be filtered; the high blood pressure that often comes with diabetes increases the strain on the filters themselves. Over time—typically, decades—the sieve wears out and starts springing leaks, letting useful protein escape into the urine. At its most basic, that's kidney disease, one of the most common ailments to afflict people with diabetes. "It turns out that a third of patients with diabetes will develop kidney damage attributable to diabetes," says Robert Toto, MD, a kidney specialist at the University of Texas Southwestern Medical Center at Dallas. According to the National Institutes of Health, almost half of new kidney disease cases each year are attributable to diabetes.
Without treatment, kidney disease inevitably progresses to what doctors call end-stage renal failure, where the sieve gives out completely. In patients who have diabetes and kidney disease, "it tends to progress even when we control blood pressure and blood sugar," Toto says. At that point, the only options left are replacing the kidney or using a mechanical one, a process better known as dialysis.
The progress of kidney disease can be dramatically slowed by a variety of drug treatments, and it's possible that intervening early enough could halt it completely. And yet there's no way to predict who is at highest risk for kidney disease. "The bottom line is if we had 100 patients with diabetes in a room, we do not have a blood test or a urine test to tell them, 'You're the 33 who are going to get kidney disease,' " says Toto. That means doctors don't know whose sieve is most likely to fail until it has already sprung a leak. With the help of an ADA grant, Toto is searching for ways to head things off before kidney disease gets out of hand.
Toto is tackling the problem by looking for indicators that would tell doctors who is most likely to develop kidney disease in the first place. To do so, he is harnessing the field of proteomics, the study of proteins in the body, to see if certain proteins appear in people who are more likely to respond to kidney treatment medications. "My team and I want to identify who's at risk so we can identify possible interventions," he says. "We'd like to find a biomarker that can distinguish someone who will respond from someone who won't. If you could predict who would respond to drug X versus drug Y, you could give them the right drug."
He's starting with urine samples collected for a previous clinical trial. In that study, he had enrolled almost 100 men and women with diabetes and kidney disease to test the effectiveness of different drugs. Urine samples were taken at the beginning of the study, in advance of treatment, to give a "before" picture of the proteins in the urine. When the study was completed, Toto knew which patients had responded well and which hadn't—the "after" picture. What Toto is trying to do now is use the "after" to figure out what, if anything, was special about the freezer full of "before" urine from the patients who responded best to the drug treatment.
It isn't that the fluid itself is special, of course. But urine has thousands of proteins, any one of which might be a biomarker—a sort of flag that appears reliably in people who respond to treatments in a certain way. The trouble is determining which of those thousands of proteins is the marker. "In general, that's what the field of proteomics is: looking for a needle in a haystack," Toto says.
The process begins by comparing haystacks—in this case, urine samples—using sophisticated machines that can identify and isolate the different proteins within. Toto is looking for proteins that all the patients who responded to drug treatment in a certain way have in common. "We need to look at a variety of needles in that haystack so we can figure out which is the most important one," he says.
If he can isolate meaningful biomarkers from the patients in his initial study, the next step would be to see if patients in a larger population have the same proteins in their urine. That would validate the results and give doctors a handy tool to check who might develop kidney disease—and to treat it before it has a chance to do great harm.
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