Discovery opens new door to solving diabetic kidney disease | MEDICUS 2023 Issue 4

Discovery opens new door to solving diabetic kidney disease

By Dr Chua Li Min, Science writer

Credit: iStock.com / saengsuriya13

Lactate, a metabolic waste product most commonly associated with post-exercise muscle aches, could also be a reliable indicator of kidney damage in diabetic patients, a multidisciplinary research team from Singapore and Japan found.

“It was a little bit surprising to see lactate emerge as a signal that can be used to identify people who go on to develop progressive kidney disease,” said Professor Thomas Coffman from the Duke-NUS Cardiovascular and Metabolic Disorders Programme, who is a senior author of the study, which was published in published in Kidney International.

Combining experiments conducted on a preclinical model with analysis of clinical data and samples from a Singaporean cohort of 230 patients with type 2 diabetes, the researchers found that lactate is key to understanding why some people with diabetes go on to develop kidney damage, a condition affecting four in ten patients with long-standing diabetes.

“This study is a great example of how we can do that, by having researchers involved in basic science collaborating directly with clinicians to uncover critical mechanistic pathways in major health conditions like diabetic kidney disease.”
Prof Thomas Coffman

“We found that the higher the lactate level was, the greater a patient’s risk of developing kidney failure,” said Coffman, who is also Dean of Duke-NUS. “So, monitoring urinary lactate could help determine prognosis and guide management of diabetic kidney disease.”

While lactate could be a promising biomarker people at risk of developing kidney disease, its levels also closely correlated with the levels of protein in urine, potentially highlighting a new mechanism that drives kidney damage.

“The lactate levels were tightly linked with albumin in the urine, which is a marker of kidney damage,” said Assistant Professor Kengo Azushima, a nephrologist with Yokohama City University Graduate School of Medicine and Duke-NUS.

When blood flows into the kidneys, it first passes through a filter that sends waste products as well as small nutrients and water into its recycling tubes, which direct the waste products into the bladder and return nutrients and water back to the bloodstream. When this filter becomes damaged, larger molecules, including proteins like albumin, can leak into these tubules. Exposure to high levels of such serum proteins may cause damage or stress, which in turn, promotes kidney disease progression.

Credit: iStock.com / Panuwat Dangsungnoen

“The high levels of lactate in the urine could be a signal indicating damage or stress to the tubule. This suggests that we might have a biomarker that reflects tubular damage, which we know has a big effect on outcome in terms of whether a patient ends up needing dialysis,” said Coffman.

Probing further, the team discovered that treatment with angiotensin receptor blockers, a common therapy for diabetic kidney disease, was effective in reducing the levels of lactate and preventing kidney injury in the preclinical models, indicating that “optimising kidney energy metabolism may be important for slowing disease progression”, suggested Coffman, who leads the global collaborative Diabetes Study in Nephropathy and other Microvascular Complications, or DYNAMO.

This National Medical Research Council-funded project, which was recently renewed, is a global collaborative project involving clinicians and scientists from six countries and 25 institutions that aims to reduce the prevalence of diabetic kidney disease. This is the first publication to result from the project’s second phase, which will focus, in part, on determining the mechanisms that lead to tubular damage.

Associate Professor Lim Su Chi, senior consultant at the Diabetes Centre at the Admiralty Medical Centre and clinical director of the Clinical Research Unit at Khoo Teck Puat Hospital, who was also part of this latest study, said, “By teasing out specific defects in renal energy pathways linked to diabetic kidney disease, this work brings us closer to precision interventions that tackle underlying disease drivers. I am hopeful future research can build on these insights to develop innovative prevention strategies.”

“Ultimately, that’s what we hope to achieve through DYNAMO—to dissect the disease mechanisms that can then be targeted for treatment,” concluded Coffman. “And this study is a great example of how we can do that, by having researchers involved in basic science collaborating directly with clinicians to uncover critical mechanistic pathways in major health conditions like diabetic kidney disease.”