Effects of Metabolic Factors, Race-Ethnicity, and Sex on the Development of Nephropathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study

Abstract

Objective: To describe the longitudinal effects of sex, race-ethnicity, and metabolic factors on the risk of developing diabetic kidney disease (DKD) in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort.

Research design and methods: Urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) by serum creatinine and cystatin C were assessed annually for up to 15 years after study entry. Markers of DKD included micro- and macroalbuminuria (UACR ≥30 mg/g and ≥300 mg/g, respectively), hyperfiltration (eGFR ≥135 mL/min/1.73 m²), and rapid eGFR annual decline (>3 mL/min/1.73 m² and/or ≥3.3%). The relationships between risk factors and DKD were evaluated longitudinally using time-to-event models.

Results: Data were available on 677 participants, average age at baseline 14 years, with a mean ± SD follow-up of 10.2 ± 4.5 years. Each 1% increment in HbA_1c conferred higher risk of microalbuminuria (hazard ratio 1.24 [95% CI 1.18, 1.30]), macroalbuminuria (1.22, [1.11, 1.34]), hyperfiltration (1.11, [1.05, 1.17]), and rapid eGFR decline (1.12, [1.04, 1.20]). Higher systolic blood pressure and baseline serum uric acid, and lower indices of β-cell function (C-peptide index and oral disposition index [oDI]), increased the risk of microalbuminuria, while higher triglycerides increased risk of micro- and macroalbuminuria. Lower oDI levels, female sex, and Hispanic ethnicity were associated with higher risk of hyperfiltration.

Conclusions: Elevated HbA_1c was a shared risk factor among all phenotypes of DKD in this longitudinal cohort of adolescents and young adults with youth-onset type 2 diabetes. Other risk factors included elevated blood pressure, triglycerides, serum uric acid, and β-cell dysfunction.

Figure 1

DKD outcomes (mean UACR and eGFR) by sex and race-ethnicity over time. Mean DKD outcomes: for up to 14 years of follow-up. Data from the “other” race-ethnicity group not included due to small numbers. NH, non-Hispanic.

Figure 2

Cumulative incidence of DKD outcomes (microalbuminuria, UACR ≥30 mg/g; macroalbuminuria, UACR ≥300 mg/g; and hyperfiltration) by sex and race-ethnicity. Kaplan-Meier cumulative incidence curves for the DKD outcomes, with number of participants at risk at 0, 6, and 12 years. The number at risk beyond year 12 declines as a function of staggered entry into the cohort from 2004 to 2008. P value for difference by sex and race-ethnicity based on log-rank test. Data from the “other” race-ethnicity group are not included due to small numbers. NH, non-Hispanic.