Proteomic analysis uncovers multiprotein signatures associated with early diabetic kidney disease in youth type 2 diabetes mellitus

Authors: PYLE, LAURA - University Of Colorado; CHOI, YE - University Of Colorado; NARONGKIATIKHUN, PHOOM - University Of Washington School Of Medicine; SHARMA, KUMAR - University Of Texas At San Antonio; WAIKAR, SUSHRUT - Boston University; LAYTON, ANITA - University Of Waterloo; TOMMERDAHL, KALIE - University Of Colorado; DE BOER, IAN - University Of Washington; VIGERS, TIMOTHY - University Of Colorado; NELSON, ROBERT - National Institute Of Diabetes And Digestive And Kidney Diseases; LYNCH, JANE - University Of Texas; BROSIUS III, FRANK - University Of Michigan; SAULNIER, PIERRE - University Of Poitiers; GOODRICH, JESSE - University Of Southern California; TRYGGESTAD, JEANIE - University Of Oklahoma Health Sciences Center; ISGANAITIS, ELVIRA - Harvard Medical School; BACHA, FIDA - Children'S Nutrition Research Center (CNRC); NADEAU, KRISTEN - University Of Colorado; VAN RAALTE, DANIEL - Amsterdam University College; KRETZLER, MATTHIAS - University Of Michigan; HEERSPINK, HIDDO - University Of Groningen; BJORNSTAD, PETTER - University Of Washington

Submitted to: Clinical Journal of the American Society of Nephrology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/8/2024
Publication Date: 10/21/2024
Citation: Pyle, L., Choi, Y.J., Narongkiatikhun, P., Sharma, K., Waikar, S., Layton, A., Tommerdahl, K.L., De Boer, I., Vigers, T., Nelson, R.G., Lynch, J., Brosius Iii, F., Saulnier, P.J., Goodrich, J.A., Tryggestad, J.B., Isganaitis, E., Bacha, F., Nadeau, K.J., Van Raalte, D., Kretzler, M., Heerspink, H., Bjornstad, P. 2024. Proteomic analysis uncovers multiprotein signatures associated with early diabetic kidney disease in youth type 2 diabetes mellitus. Clinical Journal of the American Society of Nephrology. 19(12):1603-1612. https://doi.org/10.2215/CJN.0000000000000559.
DOI: https://doi.org/10.2215/CJN.0000000000000559

Interpretive Summary: The onset of diabetic kidney disease in youth with type 2 diabetes (T2D) mellitus often occurs early and is hard to detect. Researchers in Houston, TX and colleagues analyzed thousands of proteins in blood samples from young people with T2D to find early warning signs for kidney disease. They discovered specific proteins linked to three key kidney problems: albuminuria (protein leakage in urine), hyperfiltration (abnormally high kidney function), and rapid decline in kidney function. Seven proteins were consistently linked to all three problems, suggesting they play a key role in the disease process. Using advanced modeling techniques, scientists identified unique protein patterns that strongly predict these kidney issues, much better than traditional clinical factors alone. This research helps pinpoint risk factors early and could lead to better ways to monitor and treat kidney disease in young people with diabetes. These findings could have major implications for improving the treatment of diabetic kidney disease (DKD) in young people with type 2 diabetes, by improving early detection of kidney disease and tailoring treatment according to the protein patterns (or proteomic signature). This means doctors might adjust medications or lifestyle recommendations based on their unique proteomic signature. Understanding the pathways that lead to certain protein elevation could also lead to the development of new medications that directly address the biological mechanisms driving DKD.

Technical Abstract: The onset of diabetic kidney disease (DKD) in youth with type 2 diabetes (T2D) mellitus often occurs early, leading to complications in young adulthood. Risk biomarkers associated with the early onset of DKD are urgently needed in youth with T2D. We conducted an in-depth analysis of 6596 proteins (SomaScan 7K) in 374 baseline plasma samples from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study to identify multiprotein signatures associated with the onset of albuminuria (urine albumin-to-creatinine ratio >/-30 mg/g), a rapid decline in eGFR (annual eGFR decline >3 ml/min per 1.73 m2 and/or >/-3.3% at two consecutive visits), and hyperfiltration (>/-135 ml/min per 1.73 m2 at two consecutive visits). Elastic net Cox regression with ten-fold cross-validation was applied to the top 100 proteins (ranked by P value) to identify multiprotein signatures of time to development of DKD outcomes. Participants in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study (14+/-2 years, 63% female, 7+/-6 months diabetes duration) experienced high rates of early DKD: 43% developed albuminuria, 48% hyperfiltration, and 16% rapid eGFR decline. Increased levels of seven and three proteins were predictive of shorter time to develop albuminuria and rapid eGFR decline, respectively; 118 proteins predicted time to development of hyperfiltration. Elastic net Cox proportional hazards models identified multiprotein signatures of time to incident early DKD with concordance for models with clinical covariates and selected proteins between 0.81 and 0.96, whereas the concordance for models with clinical covariates only was between 0.56 and 0.63. Our research sheds new light on proteomic changes early in the course of youth-onset T2D that associate with DKD. Proteomic analyses identified promising risk factors that predict DKD risk in youth with T2D and could deepen our understanding of DKD mechanisms and potential interventions.