Derepression of glomerular filtration, renal blood flow and antioxidant defence in patients with type 2 diabetes at high-risk of cardiorenal disease

Background: The role of antioxidant status on microvascular blood flow and glomerular filtration (eGFR) in patients with type 2 diabetes and hypertension whose risk of progressive renal disease varies by ethnicity is unknown. Methods: Adult, non-Caucasian (n = 101) and Caucasian (n = 69) patients with type 2 diabetes, hypertension and/or microalbuminuria and an eGFR > 45 mL/min/1.73 m² were randomised to receive 400 IU vitamin E and/or 20 μg selenium daily or matching placebo. eGFR (CKD-EPI) was measured at baseline, 3,6 and 12 months and renal blood flow by contrast-enhanced ultrasonography in a sub-group (n = 9) at baseline and 3 months by assessing the area under the time intensity curve (TIC). Circulating glutathione peroxidase 3 (GPx-3) activity was measured as a biomarker of oxidative defence status. Results: The time to change in eGFR was shortest with combined vitamin E and selenium than usual care (5.6 [4.0–7.0] vs 8.9 [6.8–10.9 months]; p = 0.006). Area under the TIC was reduced compared to baseline (38.52 [22.41–90.49] vs 123 [86.98–367.03]dB.s; P ≤ 0.05 and 347 [175.88–654.92] vs 928.03 [448.45–1683]dB.s; P ≤ 0.05, respectively] at 3 months suggesting an increase in rate of perfusion. The proportional change in eGFR at 12 months was greater in the group whose GPx-3 activity was above, compared with those below the cohort median (360 U/L) in the non-Caucasian and the Caucasian groups (19.1(12.5–25.7] % vs 6.5[-3.5 to 16.5] % and 12.8 [0.7 to 24] % vs 0.2 [-6.1 to 6.5] %). Conclusion: In these patients with type 2 diabetes and early CKD, antioxidant treatment derepresses renal blood flow and a rise in eGFR correlated directly with GPx-3 activity. Significance: Diabetes mellitus is the world's leading cause of end-stage renal disease which has a predilection for black and minor ethnic groups compared with Caucasians. The differences in risk despite the benefits of conventional care may be related to oxidative stress. We found that glomerular filtration and renal blood flow is suppressed when renal function is preserved in high-risk patients with type 2 diabetes. Conventional care supplemented with selenium - the co-factor for glutathione peroxidase-3 (GPx-3) - improves renal perfusion and increase glomerular filtration according to host antioxidant defence determined by GPx-3 activity. Circulating GPx-3 activity warrants further investigation as a novel biomarker of reversible haemodynamic changes in early diabetic kidney disease to better enable targeting of renoprotective strategies.