Kidney disease is a growing problem in America. Medicare spent nearly $30 billion on care for people with kidney disease in 2012. Many of these cases are caused by the high blood sugar of uncontrolled diabetes. Understanding who will develop kidney disease and how to prevent it are the holy grails of proper treatment.
“Only 10 to 40 percent [of people with diabetes] develop kidney disease,” says Robert C. Stanton, M.D., Chief of the Kidney and Hypertension Section at Joslin Diabetes Center and Associate Professor of Medicine at Harvard Medical School. “So one question: is there a marker to tell who’s going to develop it? The second question is not everybody who develops it is going to progress to end stage renal disease. So who’s going to get worse?”
Andrzej Krolewski, M.D., Ph.D., Head of the Section on Genetics and Epidemiology at Joslin Diabetes Center and Professor of Medicine at Harvard Medical School, is searching for those markers. In 2012, he published a paper detailing two new biomarkers that could be used to determine if someone with diabetes is going to develop kidney disease.
Dr. Stanton says the benefits of these types of biomarkers can be two-fold. From a clinical research standpoint, knowing with a high degree of certainty who will develop kidney disease will allow researchers to more precisely test preventative medications.
“If you’re studying a drug to see if it prevents development of kidney disease, only about 20 percent of your population is going to develop it. You need a really good drug, or you need to do a long term study to figure out if it worked or not,” he says. But if the researchers know which people are more likely to develop kidney disease at the outset of the study, then they are able to study a treatment in only those patients at risk and much more likely to find treatments that are truly preventative.
The markers would also help in treatment of patients in the clinic. If a patient has one of the biomarkers suggesting he or she will develop kidney disease, or worsen to end stage renal disease, the doctor can be more aggressive with courses of medication and other preventative measures.
“Right now, we treat everybody as if they’re going to develop kidney disease, and we treat them as if they’re going to get worse. But we really don’t know,” says Dr. Stanton. “So that being said, if we knew who was going to get worse or not, then maybe we would change our treatment one way or the other. So for instance, let’s say I have somebody under reasonable blood pressure control but not spectacular, if I know they’re going to get worse, I might really talk with them and say ‘look, there’s really strong evidence here that you’re going get worse, let’s really push this blood pressure control.’”
The same holds true in the opposite situation: there’s no need to go to extremes in treatments if the patient has a low risk of developing the disease.
Once doctors are able to better predict who will get the disease, they need a wider range of medications with which to treat the patients. Current treatments for kidney disease have been around for a while, and researchers hope newer medications will provide better outcomes. Many are searching for something more effective in the body to target with new medications.
Dr. Stanton has been studying an enzyme that plays a crucial role in many vital processes in the body. The enzyme is called G6PD, and it is the main producer of NADPH. “NADPH is necessary for a variety of major functions,” says Dr. Stanton. “Such as the entire antioxidant system. And blood pressure control relies on NADPH through nitric oxide—nitric oxide is a major regulator of blood pressure and to make nitric oxide you need NADPH. And white blood cell function depends on NADPH. And so NADPH plays a central role in a lot of processes. If G6PD doesn’t work, then not enough NADPH gets made.” Dr. Stanton’s research has shown that impaired G6PD may play a major role in the development of diabetic kidney disease and possibly in the loss of insulin-producing beta cells in the pancreas.
George King, M.D., Chief Scientific Officer at Joslin Diabetes Center and Professor of Medicine at Harvard Medical School, has been discovering new targets for many years. His previous work led to development of a drug to block a protein called Protein Kinase C beta that he and others showed to play a role in the development of diabetic complications.
More recently, he has been investigating new drug targets using information gathered from a group of people called the 50 Year Medalists who have had diabetes for 50 or more years without any significant complications. With information gathered from the people in this group, he is detecting which proteins may have played a role in keeping them free of complications, including kidney disease. If they have excess of a certain protein, for example, he is working to find a medication to increase the amount of that protein in other people with diabetes. These proteins may serve both as targets and as new markers that may be used to identify people at risk for the development and progression of diabetic kidney disease.
And a research collaboration at Joslin is testing a well-known drug’s effect on kidney disease. Allopurinol is a medication commonly used for gout that lowers uric acid. Research by many groups have demonstrated an association between high uric acid levels and progression of kidney disease. Alessandro Doria, M.D., Ph.D., Investigator in the Section on Epidemiology and Genetics and Director of the Genetics Core at Joslin Diabetes Center and Associate Professor of Medicine at Harvard Medical School, is leading a large multicenter, international study to determine whether allopurinol will slow the worsening of diabetic kidney disease. This 5-year multi-center trial received $24.3 million from the federal government in the hopes it will introduce a new and accessible medication to improve the lives of people with kidney disease.
The research being done at Joslin will help doctors to better treat patients with kidney disease, preventing them from progressing to end stage renal disease and improving the quality of life for patients with diabetes.