Relative Hypoxia and Early Diabetic Kidney Disease in Type 1 Diabetes

Abstract

The objective of this study was to compare the ratio of renal oxygen availability (RO2) to glomerular filtration rate (GFR), a measure of relative renal hypoxia, in adolescents with and without type 1 diabetes (T1D) and relate the ratio to albuminuria, renal plasma flow (RPF), fat mass, and insulin sensitivity (M/I). RO2 was estimated by blood oxygen level-dependent MRI; fat mass was estimated by DXA; GFR and RPF were estimated by iohexol and p-aminohippurate clearance; albuminuria was estimated by urine albumin-to-creatinine ratio (UACR); and M/I was estimated from steady-state glucose infusion rate/insulin (mg/kg/min) by hyperglycemic clamp in 50 adolescents with T1D (age 16.1 ± 3.0 years, HbA1c 8.6 ± 1.2%) and 20 control patients of similar BMI (age 16.1 ± 2.9 years, HbA1c 5.2 ± 0.2%). The RO2:GFR (ms/mL/min) was calculated as RO2 (T2*, ms) divided by GFR (mL/min). Whole-kidney RO2:GFR was 25% lower in adolescents with T1D versus control patients (P < 0.0001). In adolescents with T1D, lower whole-kidney RO2:GFR was associated with higher UACR (r = -0.31, P = 0.03), RPF (r = -0.52, P = 0.0009), and fat mass (r = -0.33, P = 0.02). Lower medullary RO2:GFR was associated with lower M/I (r = 0.31, P = 0.03). In conclusion, adolescents with T1D exhibited relative renal hypoxia that was associated with albuminuria and with increased RPF, fat mass, and insulin resistance. These data suggest a potential role of renal hypoxia in the development of diabetic kidney disease.

Trial registration: ClinicalTrials.gov NCT03618420 NCT03584217.

© 2020 by the American Diabetes Association.

Figures

Figure 1

RO2:GFR and relative renal hypoxia. The top panel illustrates the relationship between RO2 and GFR. A high GFR (workload) requires a high kidney oxygen availability to sustain the high energy expenditure. Therefore, whole-kidney hyperfiltration (HF) requires higher kidney oxygen availability compared with normofiltration (NF) and underfiltration (UF). The height of the smokestack plumes represents the magnitude of GFR. The bottom panel illustrates the ratio between RO2 and GFR across UF, NF, and HF. Additionally, the bottom figure demonstrates three energetic scenarios across the stages of DKD: relative hyperoxia (RO2 > GFR), balance (RO2 = GFR), and relative hypoxia (RO2 < GFR).

Figure 2

RO2:GFR across tertiles of UACR. Kidney RO2:GFR, cortex RO2:GFR, and medullary RO2:GFR across tertiles of UACR. Data presented are adjusted means (least square means) and SEs. Models are adjusted for age, sex, and HbA1c.