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Influence of antioxidant genotype and antioxidant status on progression of chronic kidney disease


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Crawford, A 2010 , 'Influence of antioxidant genotype and antioxidant status on progression of chronic kidney disease', PhD thesis, University of Tasmania.

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Chronic kidney disease (CKD) is a significant public health issue that affects an
estimated 11 percent of adults over the age of 25 years in Australia. Slowing the
progression of kidney disease is a major therapeutic challenge for nephrologists.
Oxidative stress is an imbalance between reactive oxygen species (ROS) and
antioxidants levels in cells or tissues. It has been linked to a number of diseases,
including cardiovascular disease (CVD) and CKD. Decreased antioxidant levels can be
caused by a number of factors, such as, genetic mutations that reduce the effectiveness
of the antioxidants, or toxins that deplete the concentration of antioxidant enzymes.
Antioxidants may be separated into two distinct groups, exogenous and endogenous
compounds. Important endogenous antioxidant enzymes include superoxide dismutase
(SOD), glutathione peroxidase (GPx) and catalase which together form the primary
defence system against ROS.
In recent years, the relationship between single nucleotide polymorphisms (SNPs) of
antioxidant enzymes and diseases associated with oxidative stress has been a topic of
significant interest. SNPs of the antioxidant enzymes SOD2 Alal6Val, GPx1
Pro197Leu and catalase C-262T have been associated with the pathogenesis of cancer,
cardiovascular disease and diabetes. However, links between SNPs of these enzymes
and CKD have yet to be investigated. Thus, the overall aim of the present study was to
determine associations between antioxidant enzyme SNPs, antioxidant activities and
renal function at baseline and changes thereof over a year in CKD patients.
Two major studies will be presented. The first uses a case-control design and baseline
data from the CKD patient cohort (n=230) and control subjects (n=224) to determine (a)
the frequency of specific SNPs, present in GPx, SOD and catalase genes and whether and control subjects (n=224), and (b) associations between antioxidant genotypes and
renal function. The second study uses baseline and one year data from 185 CKD
patients from the cohort and investigated whether the progression of kidney disease (i.e,
decline in eGFR) was (a) associated with specific genotypes resulting from the
aforementioned GPx, SOD and/or catalase SNPs, and (b) associated with altered plasma
GPx, RBC GPx, RBC SOD and/or RBC catalase activities.
In the case-control analysis, significantly (p=0.023) more CKD patients had the GPx
Leu/Leu genotype (n=5) compared to controls (n=0). Although not statistically
significant, patients with the GPx1 Leu/Leu or SOD2 Ala/Ala genotypes had reduced
eGFR compared with the GPx1 Pro/Leu and SOD2 ValNal genotypes. CKD patients
had significantly lower plasma GPx and RBC catalase activities compared to controls
(p<0.0001). In contrast, both RBC GPx and RBC SOD activities were significantly
higher in CKD patients (p<0.0001). In addition, in CKD patients, a significant positive
association was found between eGFR and plasma GPx activity (p<0.0001). Plasma GPx
increased (p<0.0001) and RBC GPx decrease (p<0.05) with disease progression from
Stages 1 to 5. Interestingly, when the controls were stratified according to eGFR (and
hence, Stage of CKD), 13% (30 subjects) were found to be in Stage 3 according to
Kidney Disease Outcomes Initiative (KDOQI) guidelines.
The second study showed that eGFR declined over 12 months in both SOD2 Ala/Vat
and Val/Val patients, indicating a more rapid progression of kidney disease compared to
patients with the Ala/Ala genotype (Ala/Val compared with Ala/Ala: p=0.001; VaVVal
compared with Ala/Ala: p=0.005). The progression of CKD did not appear to be
influenced by SNPs of GPx1 or catalase. There was a direct relationship between the
rate in change of plasma GPx activity and the rate of change of eGFR over the 12 month
period (p=0.025).
In summary, this is one of the largest case-control studies comparing antioxidant
enzyme genotypes and activities in CKD patients conducted to date. In addition, this
study is the first (cohort) study to investigate the role of antioxidant enzyme SNPs in the
progression of CKD. The data suggest that CKD is associated with impaired plasma
GPx and catalase activities and enhanced RBC GPx and SOD activities when compared
to controls. Secondly, although genotype frequencies were similar for patients and
controls, lower eGFR was associated with the GPx1 Leu/Leu genotype. Thirdly, CKD
patients with the SOD2 Ala/Val or Val/Val genotype had a greater decline in kidney
function over the 12 month study period when compared to patients with SOD2 Ala/Ala
genotype. These findings suggest that SOD and GPx therapies that enhance the
activities of these antioxidants may slow the progression of CICD. In addition, as 13%
of the control participants were found to have impaired kidney function (eGFR
<60mL/min/1.73m2), there appears to be significant undiagnosed CKD in Northern
Tasmania, that may warrant routine assessment of kidney function in the general

Item Type: Thesis - PhD
Authors/Creators:Crawford, A
Copyright Holders: The Author
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Copyright 2010 the Author - The University is continuing to endeavour to trace the copyright
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Available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2010 . Includes bibliographical references

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