The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes

Ron L H Har, Heather N Reich, James W Scholey, Denis Daneman, David B Dunger, Rahim Moineddin, R Neil Dalton, Laura Motran, Yesmino Elia, Livia Deda, Masha Ostrovsky, Etienne B Sochett, Farid H Mahmud, David Z I Cherney, Ron L H Har, Heather N Reich, James W Scholey, Denis Daneman, David B Dunger, Rahim Moineddin, R Neil Dalton, Laura Motran, Yesmino Elia, Livia Deda, Masha Ostrovsky, Etienne B Sochett, Farid H Mahmud, David Z I Cherney

Abstract

Objective: Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin). Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors.

Methods: Urine and serum cytokines/chemokines (Luminex platform) and GFR(cystatin) were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2)) and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2)) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n = 59).

Results: We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076).

Conclusions: Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.

Trial registration: ClinicalTrials.gov NCT01581476.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Urinary Excretion of Cytokine/Chemokines in…
Figure 1. Urinary Excretion of Cytokine/Chemokines in Adolescents with Type 1 Diabetes According to Hyperfiltration Status vs Healthy Controls.
Step-wise trends were observed for IL-12, IFNα2, IL-2, sCD40L, FGF-2, TNF-β, MIP-1α, MDC, MCP-3, GM-CSF, adjusted for age, gender, ACR and HbA1c. P-values show pair-wise comparisons with Bonferroni correction. After adjusting for plasma glucose at the time of collection, instead of HbA1c, pair-wise comparisons between normofilterers (T1D-N) and hyperfilterers (T1D-H) were no longer significant.
Figure 2. Serum Cytokine/Chemokine Signature in Adolescents…
Figure 2. Serum Cytokine/Chemokine Signature in Adolescents with Type 1 Diabetes Based on Hyperfiltration Status and Healthy Controls.
A parallel trend to urinary excretion of cytokine/chemokines was observed, although only IL-2 showed significance. P-values show pair-wise comparisons with Bonferroni correction, adjusted for age, gender and HbA1c.

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