Optimization of kidney dysfunction prediction in diabetic kidney disease using targeted metabolomics
Metabolomics have been used to evaluate the role of small molecules in human disease. However, the cost and complexity of the methodology and interpretation of findings have limited the transference of knowledge to clinical practice. Here, we apply a targeted metabolomics approach using samples blotted in filter paper to develop clinical-metabolomics models to detect kidney dysfunction in diabetic kidney disease (DKD).
We included healthy controls and subjects with type 2 diabetes (T2D) with and without DKD and investigated the association between metabolite concentrations in blood and urine with eGFR and albuminuria. We also evaluated performance of clinical, biochemical and metabolomic models to improve kidney dysfunction prediction in DKD.
Using clinical-metabolomics models, we identified associations of decreased eGFR with body mass index (BMI), uric acid and C10:2 levels; albuminuria was associated to years of T2D duration, A1C, uric acid, creatinine, protein intake and serum C0, C10:2 and urinary C12:1 levels. DKD was associated with age, A1C, uric acid, BMI, serum C0, C10:2, C8:1 and urinary C12:1. Inclusion of metabolomics increased the predictive and informative capacity of models composed of clinical variables by decreasing Akaike’s information criterion, and was replicated both in training and validation datasets.
Targeted metabolomics using blotted samples in filter paper is a simple, low-cost approach to identify outcomes associated with DKD; the inclusion of metabolomics improves predictive capacity of clinical models to identify kidney dysfunction and DKD-related outcomes.
KeywordsMetabolomics Type 2 diabetes Diabetic kidney disease Filter paper Amino acids Acylcarnitines
Diabetic kidney disease
Dried blood samples
Type 2 diabetes
Estimated glomerular filtration rate
Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers
Systolic blood pressure
Diastolic blood pressure
- U/B ratio
Ratio or urinary divided by blood concentration of measured metabolites
Leucine + isoleucine
3-Hydroxybutyryl + malonyl carnitine
3-Hydroxyisovaleril + methylmalonyl carnitine
Glutaryl + 3-hydroxyhexanoyl carnitine
All authors approved the submitted version. All the authors would like to thank the staff of the Endocrinology and Metabolism Department for all their support, particularly to Lucia Guillen-Pineda, Maria Del Carmen Moreno-Villatoro, María Guadalupe López-Carrasco and Maria Del Carmen Cruz-Lopez Adriana. We are thankful to the study volunteers for all their work and support throughout the realization of the study. OYBC would like to thank PECEM and Conacyt for their support in his research.
Research idea and study design: IIG, ICB, OYBC, CAAS, LDBP, MVA; data acquisition: RPM, DRSN, MFST, XRF, MGA, APP, MME, OYBC; data analysis/interpretation: OYBC, ICB, IIG; statistical analysis: OYBC, IIG, MVA; manuscript drafting: IIG, ICB, OYBC, MVA, CAAS, LDBP; supervision or mentorship: CAAS, LDBP, MVA. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.
Written informed consent was obtained before the examination from each patient, as well as the approval from our institutional ethics committee.
- 1.American Diabetes Association (2001) Clinical practice recommendations 2001: diabetic nephropathy (position statement). Diabetes Care 24(suppl):S69–S72Google Scholar
- 3.Penno G, Solini A, Bonora E, Renal Insufficiency Events C (RIACE) Study Group, et al (2018) Defining the contribution of chronic kidney disease to all-cause mortality in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study. Acta Diabetol 55(6):603–612CrossRefGoogle Scholar
- 49.Brindle E, O´Connor KA, Garret DA (2014) Applications of dried blood spots in general human health studies. In: Dried blood spots applications and techniques, 1st edn. Wiley, Hoboken, pp 114–129Google Scholar