A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes

Abstract

<b><i>Background:</i></b> Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. <b><i>Methods:</i></b> We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which “omics” studies will be built. Cases (<i>n</i> = 535) and controls (<i>n</i> = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m<sup>2</sup>, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques. <b><i>Results:</i></b> At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m<sup>2</sup>, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was −5.7 and 0.6 mL/min/1.73 m<sup>2</sup>, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68–0.79; <i>p</i> < 0.001). <b><i>Conclusion:</i></b> Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes

“…At the early stage (eGFR >90 mL/ min/1.73 m 2 ) and in the absence of insulin resistance, increased incorporation of unsaturated FFAs in construct of phospholipids at the sn1 carbon in fast decliners might be explained by differential upregulation of phospholipase A1 (PLA1) activity, downregulation of PLA2 activity, or both. Our earlier study in T2D suggested that upregulation of de novo lipogenesis and impaired mitochondrial β-oxidation mediated by insulin resistance when GFR is >90 mL/min/ 1.73 m 2 might be a putative mechanism of DKD progression (7). As T1D is characterized by a state of insulin deficiency, such a mechanism is unexpected to be the driving force of DKD progression at the early stage.…”

“…Cohort design and sample selection are presented elsewhere (7). In brief, 817 patients with a history of T1D and available fasting plasma samples were selected from three established cohorts, including the Steno Diabetes Center Copenhagen study (Steno, n 5 398), the Epidemiology of Diabetes Complications study (EDC, n 5 139) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n 5 281), and were randomly split in to training and validation subsets, aimed at validating the findings of the training subset (Supplementary Fig.…”

Evaluation of changes in glycemic control and diabetic complications over time and factors associated with the progression of diabetic complications in Japanese patients with juvenile‐onset type 1 diabetes mellitus

“… 32 Age, duration of diabetes, HbA1c level, UAE, and hyperfiltration have been reported as factors associated with a rapid eGFR decline in juvenile‐onset T1D. 33 , 34 , 35 Conversely, factors associated with rapid eGFR decline in Japanese patients with juvenile‐onset T1D have not been reported. This study is the first to examine this point and to reveal that the GA/HbA1c ratio is associated with a rapid eGFR decline in juvenile‐onset T1D.…”

Therapeutic Role of Curcumin in Diabetes: An Analysis Based on Bioinformatic Findings

“…In a recent clinical study in a Japanese population with type 2 diabetes, soluble EGFR as a hepatokine was indicated to be associated with insulin resistance in the liver [ 60 ]. In clinical research in 2020, over 7.6 years of monitoring and follow-up reported that the change of the annual mean EGFR in type 1 diabetes was −5.7 and in healthy people, it was 0.6 mL/min/1.73 m 2 , which demonstrates the potential rapid biomarker and possible therapeutic targets for individuals with type 2 diabetes [ 61 ]. Other previous studies indicated that EGFR has a critical role in the progression of STZ-induced diabetes in rat models [ 62 ].…”