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Diabetic kidney disease (DKD) is a common cause of kidney failure, and is associated with an increased risk of cardiovascular disease (CVD), though the underlying molecular links are less clear. The Chinese University of Hong Kong’s Faculty of Medicine (CU Medicine) led an international study to identify prognostic biomarkers and potential metabolic mechanisms linking kidney disease and heart disease to type 2 diabetes. 

This collaborative study with Amsterdam University Medical Center (UMC) and Leiden University Medical Center in the Netherlands, Baker Heart and Diabetes Institute in Australia, together with investigators in Hong Kong, Macau and mainland China, utilised metabolome analysis from the Hong Kong Diabetes Biobank (HKDB) to identify 156 metabolites associated with DKD. The study also  developed a signature of DKD metabolites that predicted CVD risk in people with type 2 diabetes, and validated it in two independent cohorts, including in Chinese and European populations. In one highlight, researchers found that triglyceride-rich lipoproteins, together with other metabolites, are associated with both DKD and incident CVD. Findings have been published in Diabetologia, the official journal of the European Association for the Study of Diabetes (EASD).

CVD is the major cause of mortality in DKD patients

Diabetes is the most common cause of chronic kidney disease and contributes to half of the new renal failure cases in Hong Kong every year. It is associated with a two- to four-fold increase in risk of CVD, and reportedly even higher in DKD patients. CVD is a major cause of death among DKD patients.

Professor Juliana Chan Chung-ngor, Chair Professor of Medicine and Therapeutics and Head of Division of Clinical Pharmacology at CU Medicine said, “Despite multifactorial management and agents with pleiotropic cardiorenal benefits, DKD prognosis remains poor. With better understanding of the potential metabolic links between DKD and CVD, we will be able to make a more precise prediction of heart disease risk in DKD patients and to provide more informed therapeutic suggestions.”  

“Identifying biomarkers can improve the prediction of future complications among people with diabetes,” noted Professor Alicia Jenkins, Head of Diabetes and Vascular Medicine at the Baker Heart and Diabetes Institute in Melbourne, Australia. “We are glad to see the study highlights the potential utility of subclasses of lipoproteins as potential biomarkers for kidney disease and cardiovascular risk in diabetes.”

Research team found 22 metabolites linked to both DKD and CVD risks

The CU Medicine team conducted an analysis in a prospective cohort of 1,991 individuals with type 2 diabetes, who were quantified for 170 metabolites using NMR spectroscopy, with a median 5.2 years of follow-up. All subjects were recruited from the Hong Kong Diabetes Biobank (HKDB). Results showed 156 metabolites profiled were associated with reduced kidney function or proteinuria, of which 75 were also associated with incident CVD. Among these 75, 22 remained nominally significant after further adjusting for chronic kidney disease and severely increased albuminuria. The metabolic markers identified include triglyceride-rich lipoproteins, small high-density lipoprotein (HDL), leucine and albumin.    

Researchers developed a signature of metabolites that predict heart disease risk in people with diabetes in the Hong Kong Diabetes Biobank, and then replicated this biomarker signature using samples from the Hong Kong Diabetes Register, as well as the Hoorn Diabetes Care System in the Netherlands.

Professor Ronald Ma Ching-wan, S.H. Ho Professor of Diabetes and Head (Academic Affairs) in the Division of Endocrinology and Diabetes at CU Medicine, and corresponding author of the analysis,

said, “Metabolomic biomarkers provided comparable predictive utility to traditional risk factors and improved CVD risk stratification over established prediction models. Our study provided new insights on the links between kidney disease and heart disease risk, and we are pleased to share these findings ahead of World Kidney Day on March 14.”  

“Our group has performed extensive research in the area of genetics and other ‘omics’ using the Hoorn Diabetes Care System cohort,” remarked Associate Professor Leen ‘t Hart, lead scientist of “omics” research for the Hoorn studies at the Leiden University Medical Center. “We are delighted that our research objectives and datasets are so well aligned with the Hong Kong Diabetes Biobank, which has facilitated our collaborations in these areas to bring new insights on biomarkers for diabetes complications.”

Professor Ma added, “This study also highlights the importance of establishing biobanks to advance understanding disease mechanisms and biomarker discovery, and the potential synergies between different cohorts and biobanks. Without these well-established biobanking initiatives in Hong Kong and the Netherlands, these collaborative studies and findings would not have been possible.”

This work was supported by the Research Grants Council Research Impact Fund (R4012-18), as well as other research funds.