Despite the implementation of reno-protective therapies, drugs that reduce the amount of protein in urine, ESRD is still a prominent risk for people with type 1 diabetes, which is why Andrzej Krolewski, M.D., Ph.D., Head of the Section on Genetics and Epidemiology and Associate Professor of Medicine at Harvard Medical School, is implementing a new approach towards fighting ESRD. Dr. Krolewski’s approach focuses on the slope – or the rate at which renal function decline occurs – of renal function to assess and search for new therapies to treat ESRD.
This new approach derives from research in Dr. Krolewski’s lab that shows proteinuria, or protein in a patient’s urine, is a symptom of kidney disease, but not the cause or predictor of kidney disease. Their research also demonstrated that proteinuria will not necessarily occur if a patient has kidney disease. Dr. Krolewski concluded that the actual underlying cause of ESRD is declining renal function and proteinuria is merely a symptom that can accompany kidney disease in various degrees.
These findings defy the proteinuria centered model that has been used for the last 150 years, and illustrate that physicians have been approaching diabetic kidney disease from the wrong angle. According to Dr. Krolewski, to properly address diabetic kidney disease, physicians need to conduct clinical trials that measure the slope of renal function over several years.
“If you really want to address this issue, you need a clinical trial that doesn’t measure protein in urine, but measures the slope or the decline in renal function,” said Dr. Krolewski. “The problem is the decline in renal function does not change overnight. To see this, you need perhaps five or six years of clinical trials.”
Although it can be challenging to correctly examine diabetic kidney disease, Dr. Krolewski has a found a way by using Joslin’s “bio bank,” which is a collection of blood and urine specimens from every patient involved in his kidney studies. These samples are only kept for clinical use with the patients’ permission. The bio bank allowed Dr. Krolewski to study kidney disease in human models as opposed to animal models, and this is crucial because animal models cannot accurately mimic the progression of kidney disease in humans. The bio bank also enabled Dr. Krolewski and his lab to follow the progression of kidney disease over an extended period time, which is critical to understanding the development of diabetic kidney disease.
“Kidney complications develop after 10 – 15 years of diabetes, so you need long term observations to see which patients develop severe kidney problems and which patients do not,” commented Dr. Krolewski. “Joslin has a large population of diabetes patients who continue to come to Joslin for care over a long period of time, and that is the one of major advantages that [Joslin] has over any other clinical center in the world.”
With the specimens from his bio bank, Dr. Krolewski also developed a diagnostic test that predicts how quickly a patient will lose renal function by measuring their serum tumor necrosis factor receptor (TNFR) levels. High concentrations of TNFR1 and TNFR2 are shown to be strongly associated with the risk for developing ESRD. The patent for this test was sold to EKF Diagnostics, who plan to further develop this test to be used in routine care for patients with diabetes to identify those at risk for ESRD.
In addition to disproving the proteinuria centered model and developing a diagnostic test, Dr. Krolewski and his colleagues also conducted an instrumental study that showcased the implications from their discoveries. During this study they monitored and analyzed how glycemic control impacts a patient’s risk for developing ESRD. They found that patients who improved their glycemic control were able to significantly decrease their risk for ESRD, while patients who did not improve or decreased their glycemic control were at a much higher risk for developing ESRD.
Although glycemic control is currently the only treatment for ESRD, Dr. Krolewski believes that physicians can use these findings to help patients at risk for ESRD by working with them to improve their glycemic control. In the past, people assumed that once a patient presented with proteinuria, it was too late for glycemic control to have any effect on declining renal function, but Dr. Krolewski says this is not the case anymore.
“Our research is showing is that for patients with proteinuria and poor glycemic control, the doctor and patient should do everything to improve glycemic control and expect results three to five years later, [but] not right away,” he said.
Dr. Krolewski and his team are continuing their research by examining different pathways for drugs, conducting genetic research that can help understand the mechanisms of renal function decline and executing various metabolic studies. They hope this research will lead to the development of a drug that can treat the decline in renal function, which is essential in postponing the development of ESRD and lessening the risk of diabetic kidney disease for people with type 1 diabetes.