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Predictive Change in Renal Function and Glutathione Peroxidase-3 Activity in Type 2 Diabetes

47 Pages Posted: 19 Feb 2019

See all articles by Karima Zitouni

Karima Zitouni

University of London - Institute of Infection and Immunity

Mia Steyn

NHS Foundation Trust - St. Georges University Hospitals

Frank J. Kelly

University of London - MRC-PHE Centre for Environment and Health; University of London - Analytical, Environmental and Forensic Sciences Department

Paul Cook

University of Southampton - University Hospital Southampton NHS Foundation Trust

Irina Chis Ster

University of London - Institute of Infection and Immunity

Kenneth Anthony Earle

NHS Foundation Trust - St. Georges University Hospitals; University of London - Institute of Biomedical & Medical Education

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Abstract

Background: Hyperglycaemia causes oxidative stress which accelerates the loss of renal function. In experimental studies, antioxidant enzymes such as glutathione peroxidase (GPx-3) mitigate this effect and clinical studies suggest that antioxidant therapy stimulates an increase glomerular filtration (eGFR) in advanced disease.  It is unknown whether these changes occur with preserved renal function or varies between groups with differences in renal disease susceptibility.    

Methods: Patients with type 2 diabetes of Caucasian and non-Caucasian heritage with an eGFR >45mls/min/1.73m2 with microalbuminuria and/or hypertension were randomized in four groups to receive selenium and vitamin E together, individually or as double-placebo with usual care. A series of mixed models were fit to assess treatment efficacy and modulation by GPx-3 activity status on eGFR over 12 months.    

Findings: Estimated glomerular filtration increased in all treatment groups with the time to peak rise (TPR) being shortest with both antioxidants given together (5.6 [4-7] months) compared to double-placebo (8.9 [6.8-10.9] months; p=0.006) and was longer for non-Caucasian compared with the Caucasian group regardless of the intervention. Patients with low GPx-3 activity (<360 U/L) experienced a 2-fold greater rise in eGFR with the double-active intervention. A sustained increase in eGFR occurred in patients of non-Caucasian heritage treated with selenium alone and in those with high GPx-3 activity (>360 U/L) receiving usual care after adjusting for age, ethnicity and albuminuria (p=0.003).    

Interpretation: The activity of GPx-3 is a biomarker of the rise in eGFR that occurs with antioxidants and usual care.  These biochemical and physiological markers could be useful in tailoring nephroprotective treatments for  patients with type 2 diabetes at risk of renal dysfunction.

Trial Registration Number: ISRCTN 97358113    

Funding Statement: This research is supported by a grant from Dialysis Clinic Inc (C-3305) and the National Institutes of Health Research (UKCRN ID: 8432).  

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: The protocol was approved by the UK National Health Service (NHS) National Research and Ethics Committee and written informed consent was obtained from all trial participants prior to enrollment.

Suggested Citation

Zitouni, Karima and Steyn, Mia and Kelly, Frank J. and Cook, Paul and Ster, Irina Chis and Earle, Kenneth Anthony, Predictive Change in Renal Function and Glutathione Peroxidase-3 Activity in Type 2 Diabetes (February 15, 2019). Available at SSRN: https://ssrn.com/abstract=3335041 or http://dx.doi.org/10.2139/ssrn.3335041

Karima Zitouni

University of London - Institute of Infection and Immunity

London
United Kingdom

Mia Steyn

NHS Foundation Trust - St. Georges University Hospitals

London
United Kingdom

Frank J. Kelly

University of London - MRC-PHE Centre for Environment and Health

London, SE1 9NH
United Kingdom

University of London - Analytical, Environmental and Forensic Sciences Department

London
United Kingdom

Paul Cook

University of Southampton - University Hospital Southampton NHS Foundation Trust

University Rd.
Southampton SO17 1BJ, Hampshire SO17 1LP
United Kingdom

Irina Chis Ster

University of London - Institute of Infection and Immunity

London
United Kingdom

Kenneth Anthony Earle (Contact Author)

NHS Foundation Trust - St. Georges University Hospitals ( email )

London
United Kingdom

University of London - Institute of Biomedical & Medical Education ( email )

London
United Kingdom

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