BIOMARKERS OF AGEING AND FRAILTY IN THE DIALYSIS COHORT

PhD ThesisINTRODUCTION: There appears to be an accelerated ageing process seen among patients with end stage kidney disease. They often exhibit premature aged phenotypes which include frailty, sarcopenia and protein energy wasting. These phenotypes are associated with increased morbidity and mortality. The exact reason for premature ageing in this cohort has been poorly understood. We hypothesised that biomarkers of cellular senescence and biological age may be associated with features of ageing observed in dialysis patients; in particular the frailty phenotype. OBJECTIVES: The aim of the study was to investigate the relationship between biomarkers of ageing; telomere length (TL) and DNA methylation (DNAm) status with frailty phenotype. METHODS: All patients had their DNA extracted from peripheral leucocytes and frailty was measured by using the Fried Frailty Phenotype criteria. Extracted DNA was used to measure TL by quantitate polymerase chain reaction and DNAm status was measured by sodium bisulphite conversion with targeted sequencing of 48 CpG sites. Dialysis patients were followed up after a year for repeat telomere length and frailty assessment. RESULTS: Between the period of December 2015 to July 2018, 339 patients were recruited. Of these 335 patients had TL and 253 patients had DNAm status measured successfully. Frailty assessment at baseline were completed in 299 patients and 155 patients at 1 year. Repeat TL at 1 year was measured in 136 patients. A univariate analysis found that baseline TL was longer in the control group of healthy donors in comparison to dialysis patients, p=0.006 but this significance was lost after adjusting for age and gender. A decrease in mean TL (p=0.001) and increased mean DNAm age (p=0.001) was observed in the frail group. TL and DNAm age were significantly associated with frailty in a univariate analysis, p=0.010 and p= 0.014 respectively but only TL remained significant in a multivariate analysis to predict frailty, p=0.018. A receiver operating characteristic curve analysis demonstrated that TL was a significant predictor of frailty, p=0.0010 with an area under the curve of 0.64. A decrease of TL by 1 standard deviation was associated with a 52.2% increase risk of frailty when adjusted for age and gender in the dialysis cohort. CONCLUSION: The study supports the hypothesis that TL; a biomarker of ageing is better associated with frailty, an ageing phenotype in comparison to DNAm age in dialysis patients