*4.3. Oxidative Stress*

This model of CKD was accompanied by a reduction of serum GPx activity suggesting depression in systemic antioxidant capacity. This did not translate into systemic oxidative stress, and thus, may be an indication of an early stage of the disease process or a degree of adaptation of the oxidative system to uraemia. The observation of reduced GPx was in line with the reports of Romeu et al. [57]. Serum TBARS in uraemic group were comparable to sham, indicating no systemic oxidative damage at this stage of CKD. This does not exclude an initial acute e ffect as a result of uraemia but may also sugges<sup>t</sup> compensation or adaptation during the first weeks. This is in contrast to reports of increased systemic TBARS and GSSG in patients with CKD [58]. Patients with CKD were characterised by increased markers of systemic oxidative stress [59], such as increased level of serum lipid peroxidation markers [58], GSSG [57] and protein carbonyls [60]. Blood is rich in both enzymatic and non-enzymatic antioxidant components to detoxify reactive oxygen species (ROS). However, in the event of increased cellular oxidative activity, excess ROS can spill into the circulation initiating a cycle of ROS induced ROS generation; ROS mediated loss of anti-oxidant capacity and culminate in overt systemic oxidative stress [61]. Therefore, the depression in systemic GPx activity here could be an early event that increases the vulnerably to systemic oxidative stress later in CKD if there is no adequate compensation. Increased kidney GSSG levels were found in uraemic animals in this study. GSH is a reductant that reduces free radicals in oxidation reactions leading to the generation of GSSG. Hence, increased GSSG levels may be indicative of enhanced pro-oxidant activity.

The improved iron deficiency anaemia by iv ferumoxytol in the present study enhanced GPx activity considering the increased evidence of systemic lipid peroxidation, indicating potential long-term benefit of iv iron to CKD patients with ID anaemia. There are conflicting reports regarding the impact of iv iron on oxidative stress in CKD patients [5], as it is associated with some increase or no e ffect on systemic oxidative stress [62,63]. These conflicting reports could be attributed to di fferences in iron formulation and the dosage used [64,65]; severity of the disease and whether or not patient is on dialysis [66]. Following iv administration of 100 mg iron sucrose to stage 3 or 4 CKD patients, Agarwal et al. [66] found increased lipid peroxidation within 15 to 30 min that completely resolved within 24 h. Unequivocally, iv iron precipitates acute oxidative toxicity as demonstrated by the recent report of Kuo et al. [67]. In their in vitro studies, the investigators reported transient increases in ROS generation between 1–3 h and enhanced NADPH oxidase activity within 30–60 min following 160 μg/mL iron sucrose supplementation, which normalised after 4 h. Administration of the antioxidant, n-acetylcysteine, together with iron therapy attenuated ROS production and its associated endothelial dysfunction [67]. Hence, antioxidant therapy use concomitantly with iv iron clinically may alleviate acute iron oxidative toxicity and facilitate the appreciation of the many chronic benefits highlighted in this study.
