Investigation of novel biomarkers associated with renal disease

Abstract

This thesis describes a body of work examining associations between retinal biomarkers (retinal microvascular parameters [RVP] and retinal layer thickness measurements) and measures of renal function and damage (estimated glomerular filtration rate and urinary albumin to creatinine ratio). Retinal biomarkers have previously been associated with the most significant causes of chronic kidney disease (CKD), hypertension and diabetes, and the most important effect of CKD, cardiovascular disease. As a result of recent advances in retinal imaging technologies, and the routine collection of fundus photographs and optical coherence tomographs at diabetic eye screening clinics and high-street opticians, retinal biomarker measurement has become a potentially cost-effective source of structural information from the microvasculature and neuronal layers in vivo that can be collected semi-automatically and non-invasively as part of routine eye screening or measured from pre-existing images. This may allow for cost-effective improvements in the early prediction of symptomatic CKD, and/or progression of CKD, helping to target earlier treatment initiation, and facilitating new therapeutic avenues. To assess the association between retinal arteriolar and venular calibre, arterio-venous ratio (AVR), fractal dimension, and tortuosity were measured and their associations with estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (ACR) were tested in population-based and clinically derived populations. Measurements of retinal thickness were also taken and their association with eGFR tested. Overall, no evidence of an association between retinal microvascular calibres and renal function (eGFR) or damage (ACR) was found independent of known confounding influences. Cross-sectional analyses of UK biobank data showed that sparser retinal microvascular networks (lower arteriolar and venular fractal dimensions) were associated with an increased risk of ACR > 3mg/mmol. In a prospective cohort, RVPs did not predict reductions in renal function in individuals with type 2 diabetes. These findings do not provide evidence for associations between measures of retinal microvascular calibre and CKD or for predictive value of RVP for the progressive loss of renal function in diabetes. Associations between both renal health and RVP and two potential confounding factors (diet and cognitive function) were also assessed and models of the association between RVP and ACR were constructed to adjust for these factors. The results of these analyses did not provide evidence for an association between Alzheimer’s disease and eGFR < 60mL/min/1.73m2 , nor a clinically significant association between cognitive function and ACR > 3 mg/mmol. Consistent with this, models of the association between RVP and ACR were not altered following adjustment for cognitive function. In the Irish Nun Eye Study, adherence to an unhealthy dietary pattern was associated with poorer renal function but no association between the dietary intake of various food groups and ACR was found in the UK biobank population and associations between RVP and ACR were not altered following adjustment for dietary intake. The work presented in this thesis did not, therefore, provide sufficient evidence that either cognitive function or dietary intake warrant inclusion as confounding variables in future studies of RVP in CKD. Finally, novel associations between inner retinal layers and eGFR < 30 mL/min/1.73m2 were found in conjunction with altered fractal dimensions in the retinal microvasculature which supplies the inner retinal layers. Longitudinal analysis of this association may be warranted to assess the predictive potential of retinal thickness measurements for CKD.

Date of Award	Jul 2020
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Gareth McKay (Supervisor) & Peter Maxwell (Supervisor)