Kidney Hyperfiltration and Mitochondrial Changes Are Associated With eGFR Decline in Young People With Type 1 Diabetes

Abstract

OBJECTIVES: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA to nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function. METHODS: Eighty adolescents were studied at baseline (mean [SD] age 14.2 [1.5] years; mean diabetes duration 6.7 [3.0] years) and at follow-up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR, and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR. RESULTS: Overall, 4.2% of participants had diabetic kidney disease at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73 m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration, and HbA1c (hyperfiltration -1.46 [3.07] mL/min/1.73 m2/year vs non-hyperfiltration -0.51 [2.48] mL/min/1.73 m2/year, P = .02). Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73 m2/year) compared to those without hyperfiltration (odds ratio 14.11 [95% CI 2.30-86.60], P = .004). Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modeling. CONCLUSION: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function.