Tackling the link between diabetes and kidney disease

13 October 2020

In Hong Kong, 52 per cent of new patients requiring dialysis treatment or renal replacement have diabetes as the cause of kidney failure – a challenge that Professor Sydney Tang (Croucher Senior Medical Research Fellowship 2019, Croucher Fellowship 1996) seeks to address.

His research focuses on why and how diabetes, a metabolic disorder, causes kidney disease. “Diabetes patients develop a number of health complications and kidney disease is quite prevalent among them. We estimate that up to one-third of diabetes patients go on to develop diabetic kidney disease,” said Tang, who is Chair Professor of Renal Medicine and Yu Professor in Nephrology in the Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong.

He added: “My focus for the Croucher Fellowship [Senior Medical Research] is on kidney inflammation in diabetic kidney disease and exploring new pathways of organ injury.” However, the project has been delayed because of the COVID-19 pandemic.

Yet COVID-19 has also acted as a reminder of the urgency for such research. People with kidney disease and those who have undergone a transplant have been found to be at higher risk of developing serious complications following the viral infection and account for a high percentage of novel coronavirus disease fatalities, according to various medical studies and government agencies.

Meanwhile, the prevalence of chronic kidney disease (CKD) in China is estimated at 10.8 per cent of its total population. This translates to over a 100 million people with different levels of reduced kidney function.

Diabetes is the most common cause of CKD and a leading cause of kidney failure worldwide. The World Health Organisation estimates that worldwide between 5 million and 10 million people die of kidney disease each year, while in 2015 kidney failure alone killed 1.2 million individuals.

Toll-like receptor 4 and kidney disease

Tang’s team has found one of the receptors, named toll-like receptor 4, that mediates the inflammatory response in the kidney due to diabetes.

He explained that high glucose levels lead to the binding of glucose to proteins resulting in an increased formation of advanced glycation end products (AGEs). High glucose in the cells and AGEs could induce sterile inflammation, giving rise to the leakage of protein in urine. Over time, proteinuria leads to a deterioration of kidney function because it can cause injury to kidney cells and stimulates the cells to express an inflammatory phenotype.

“Our research shows that kidney patients overexpress toll-like receptor 4 in the kidney tubule cells. We found this to be true in animals too, using a diabetic mouse model,” Tang said.

“We found that if we knock out this particular receptor from the animals and induce diabetes, they would actually develop a less severe form of kidney disease compared to animals without deletion of this receptor.”

Using cell culture models, the team also found that if toll-like receptor 4 expression is silenced in kidney tubule cells in the petri dish and then exposed to high glucose, the cells would manifest lower levels of inflammatory markers, therefore validating the notion that inflammation plays a crucial role during the development of diabetic kidney disease. However, the finding needs more research and development before it is applied in clinical practice, Tang said.

Proteinuria and treatment of IgA nephropathy

Chronic progressive proteinuria is one of the most common forms of chronic kidney disease and, along with diabetic nephropathy, is a leading causes of end-stage kidney disease in many developed countries. Tang has devoted much of his career to studying conditions that lead to proteinuria, and to developing novel treatments for them.

“The protein in the urine stimulates tubular cells to enter a pro-inflammatory and pro-fibrotic state, leading to progressive loss of kidney function,” Tang said. “And this is regardless of the original kidney disease, such that it could be due to primary glomerulopathy, diabetic kidney disease, or other conditions such as lupus nephritis, as long as the condition gives rise to significant and sustained proteinuria.”

Tang has been investigating anti-inflammatory treatment for IgA nephropathy, a condition that occurs when an antibody called immunoglobulin A (IgA) builds up in the kidney, resulting in local inflammation that, over time, can hamper the kidney’s ability to filter waste products from the blood. IgA nephropathy is most prevalent in Asia and Asia Pacific.

“Mycophenolate mofetil is one of the immunosuppressants widely used in organ transplantation to prevent organ rejection by reducing immunity of the body. We found that this agent also reduces severity of kidney disease in selected Chinese IgA nephropathy patients,” Tang said, cautioning that not all patients respond to this form of treatment, particularly if advanced CKD has already been established.

The use of mycophenolate has received wide recognition in China and studies he has been involved in have shown that its combination with low-dose corticosteroid is non-inferior to the standard-dose corticosteroid. This therapy will be featured as a practice point in a forthcoming international clinical practice guideline to be published by the non-profit Kidney Disease: Improving Global Outcomes (KDIGO) organisation.

Tang first developed his interest in this research field in 1996, when he was a Croucher Fellow at Guy’s Hospital, University of London, in the UK. Since then his time has been split between his research, clinical practice, and teaching.

“The kidney is a complicated organ with numerous types of resident and infiltrating cells and therefore it is difficult to find a drug that is overwhelmingly effective. There are so many cell types and different inflammatory and fibrotic processes going on that there really is no single drug for the treatment of many kidney diseases,” he said.

However, Tang’s work on chronic kidney diseases, and in particular diabetic nephropathy, has made significant findings that can better manage the treatment of renal patients and help mitigate long-term impacts of these highly prevalent illnesses.

Professor Sydney Tang graduated from the University of Hong Kong (HKU) in 1991, and obtained MD and PhD degrees from HKU in 2001 and 2005, respectively. He underwent his training in Nephrology and Internal Medicine at the University of Hong Kong; King’s College London, UK; and the University of Washington, WA, US. He joined HKU as Clinical Associate Professor in 2006 and was promoted to Clinical Professor in 2010. He is also Chair of Renal Medicine and Yu Professor in Nephrology, Department of Medicine, Li Ka Shing Faculty of Medicine. He was awarded the Faculty Teaching Medal in 2009 and Outstanding Researcher Award in 2015. He received a Croucher Senior Medical Research Fellowship in 2019 and a Croucher Fellowship in 1996.

To view Professor Tang’s Croucher profile, please click here