Oxidative stress is increasingly recognised as an important contributor to the progression and systemic complications of chronic kidney disease (CKD). Increased generation of reactive oxygen species combined with inadequate antioxidant defence may result in lipid peroxidation, oxidative DNA damage, inflammation and cardiovascular complications. Objective: To compare oxidative stress and antioxidant defence markers between patients with CKD and healthy controls and to evaluate their relationship with the severity of renal dysfunction. Materials and Methods: This hospital-based analytical case–control study included 120 participants, comprising 60 patients with CKD and 60 age- and sex-matched apparently healthy controls. Serum malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were evaluated as markers of lipid peroxidation and oxidative DNA damage. Superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and total antioxidant capacity were assessed as indices of antioxidant defence. Renal function was evaluated using serum creatinine, blood urea and estimated glomerular filtration rate (eGFR). CKD patients were further analysed according to disease stage and dialysis status. Results: MDA levels were significantly higher in CKD patients than controls (6.90 ± 1.84 vs 3.20 ± 0.91 nmol/mL; p<0.001). Similarly, 8-OHdG was significantly elevated (12.80 ± 4.16 vs 5.60 ± 1.87 ng/mL; p<0.001). Antioxidant defence was markedly impaired: SOD was 4.90 ± 1.31 versus 7.80 ± 1.52 U/mL, catalase 34.1 ± 9.7 versus 51.6 ± 11.2 U/mL, GPx 425 ± 118 versus 612 ± 134 U/L and total antioxidant capacity 0.89 ± 0.24 versus 1.42 ± 0.31 mmol/L in CKD patients and controls, respectively (all p<0.001). MDA and 8-OHdG progressively increased with advancing CKD stage, whereas SOD declined. eGFR correlated negatively with MDA (r=−0.68, p<0.001) and 8-OHdG (r=−0.62, p<0.001). Conclusion: CKD is associated with substantial oxidative stress and impairment of endogenous antioxidant defence. The progressive increase in oxidative injury with declining renal function suggests that MDA and 8-OHdG may serve as supplementary biomarkers of oxidative burden and disease severity in CKD.

Epigenetic mechanisms may contribute to persistent oxidative and inflammatory disturbances in chronic kidney disease (CKD). DNA methylation and transcriptional regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway are particularly relevant because they may influence cellular ability to respond to oxidative stress. Objective: To assess global DNA methylation and expression of Nrf2-mediated antioxidant pathway genes in patients with CKD and examine their association with renal function and oxidative stress. Materials and Methods: Sixty patients with CKD and 60 age- and sex-matched healthy controls were studied. Global DNA methylation was quantified as 5-methylcytosine (5-mC). Relative messenger RNA expression of NFE2L2/Nrf2 and downstream antioxidant genes HMOX1, NQO1, SOD1, CAT and GPX1 was assessed. Oxidative stress was evaluated using malondialdehyde and 8-hydroxy-2′-deoxyguanosine. Relationships among methylation, gene expression, oxidative stress, eGFR, CKD stage and dialysis status were analysed. Results: Mean global 5-mC content was significantly lower among CKD patients than controls (3.74 ± 0.68% vs 4.62 ± 0.71%; p<0.001). Global methylation was 3.89 ± 0.63% in non-dialysis CKD and 3.38 ± 0.58% in maintenance haemodialysis patients compared with 4.62 ± 0.71% among controls. Expression of NFE2L2 was reduced to 0.63 ± 0.21 relative to 1.00 ± 0.24 in controls. HMOX1, NQO1, SOD1, CAT and GPX1 expression were also significantly reduced (all p<0.001). Global 5-mC decreased progressively from 4.20 ± 0.51% in Stage 3a to 3.38 ± 0.58% in Stage 5D. eGFR correlated positively with global 5-mC (r=+0.57, p<0.001), whereas MDA (r=−0.55) and 8-OHdG (r=−0.51) correlated negatively with global methylation. MDA was inversely associated with NFE2L2 expression (r=−0.46, p<0.001). Conclusion: CKD is associated with global DNA methylation abnormalities and suppression of the Nrf2-mediated antioxidant transcriptional response. Their progressive alteration with worsening renal function supports a close relationship between epigenetic dysregulation, oxidative stress and CKD severity.

Background: - The safety and efficacy of transcatheter aortic valve replacement (TAVR) in patients who have severe aortic stenosis and aortic annuli larger than that specified in manufacturer guidelines and who have been rejected for surgery is unknown. Methods: All patients who underwent TAVR with a 34-mm Evolut valve (Medtronic, Minneapolis, Minn.) at a single center from 2016-2022 were included. The cohort (n=530) was divided into an off-label group (cases, n=36), defined by an aortic annulus perimeter above the manufacturer’s recommended range for the 34-mm Evolut valve (>94.2 mm), and an on-label group (controls, n=494). All patients in the off-label group were deemed prohibitive surgical risk and were declined for surgical aortic valve replacement by the Heart Team. All patients were followed for the clinical outcomes of in-hospital mortality, permanent pacemaker (PPM) implantation, aortic valve reintervention, device migration, and paravalvular leak (PVL). Results: Cases had a statistically significant larger annular perimeter than controls (97.2 vs 84.7 mm; P<0.0001). Most cases (88.9%) and controls (98.6%) had mild or no PVL, and 94.4% of cases survived in-hospital. Cases had higher rates of moderate/severe PVL (11.1% vs 1.4%, P≤0.0001), device migration (5.6% vs 0.3%, P≤0.0001), and in-hospital mortality (5.6% vs 0.8%, P=0.0094) reflecting the increased anatomic and procedural risk associated with extreme annular enlargement, but similar incidences of aortic valve reintervention (0.4% vs 0%, P=0.70) and PPM (8.3% vs 13.2%, P=0.37).  Conclusions: Self-expanding TAVR valves can be used safely and effectively to treat patients with an oversized aortic annulus who are rejected for surgical intervention. The findings of this study can help guide management in these patients who lack alternatives.