Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach

Abstract

Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful.

Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes.

Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m² and/or urinary albumin-creatinine ratio ≥3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline.

Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27–2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16–1.69); myoglobin (OR 1.57, 95% CI 1.30–1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17–1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03–1.98]) but not after further adjustments for cardiovascular risk factors.

Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

Keywords:

• Albumin-creatinine ratio
• biomarker
• diabetic kidney disease
• glomerular filtration rate
• proteomics
• risk factor
• type 2 diabetes mellitus

Author contributions

ACC conceived the study, drafted the manuscript, and interpreted data. CN analysed the data and revised/edited the manuscript. JS, JJC, EI, and TF contributed to methodology and reviewed/edited the manuscript. UR contributed with data from ULSAM and read and reviewed/edited manuscript. CJÖ and FHN reviewed/edited the manuscript and collected the CARDIPP data. Data from the PIVUS study were collected by LL, and he also reviewed/edited the manuscript. JÄ interpreted data, reviewed/edited manuscript, contributed to discussion, and provided funding.

Disclosure statement

The study was investigator-initiated and -driven. Erik Ingelsson is a scientific advisor for Precision Wellness, and has received consulting fees from Olink Proteomics for work unrelated to the present project. The company had no influence over design, analysis, or interpretation of data in the present study, and did not provide any funding for the study. The other authors report no conflicts of interests.

Additional information

Funding

This study was supported by The Swedish Research Council, Swedish Heart-Lung Foundation, the Marianne and Marcus Wallenberg Foundation, the European Union Horizon2020 (grant number 634869), Dalarna University and Uppsala University. CN was supported by an EFSD/Lilly Young Investigator Award. TF has funding from the Swedish Heart and Lung Foundation and the Swedish Research Council. The funding sources did not play any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Dr Ärnlöv is the guarantor of this work, had full access to all the data, and takes full responsibility for the integrity of data and the accuracy of data analysis.

Notes on contributors

Axel C. Carlsson

Axel C. Carlsson, MSc, PhD is an associate professor at the Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden.

Christoph Nowak

Christoph Nowak, PhD, BM BCh, Dipl-Psych, is a post-doctoral researcher at the Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden.

Lars Lind

Lars Lind, MD, PhD is a professor at the Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Carl Johan Östgren

Carl Johan Östgren, MD, PhD is a professor at the Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Fredrik H. Nyström

Fredrik H. Nyström, MD, PhD is a professor at the Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

Johan Sundström

Johan Sundström, MD, PhD is a professor at the Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Juan Jesus Carrero

Juan Jesus Carrero, MSc Pharm, PhD is a professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Ulf Riserus

Ulf Riserus, PhD is a professor at the Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Uppsala, Sweden.

Erik Ingelsson

Erik Ingelsson, MD, PhD is a professor at the Stanford Cardiovascular Institute, and the Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, and the Molecular Epidemiology and Science for Life Laboratory, Uppsala University

Tove Fall

Tove Fall, PhD, is a associate professor at the Department of Medical Sciences, Molecular Epidemiology and SciLife Laboratory, Uppsala University, Uppsala, Sweden.

Johan Ärnlöv

Johan Ärnlöv, MD, PhD, is a professor of family medicine at the Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden, and the School of Health and Social Studies, Dalarna University, Falun, Sweden.