Abstract
Despite advances in care between 30-40% of people with diabetes develop diabetic kidney disease (DKD) which is one of the leading causes of end-stage renal disease (ESRD). DKD is associated with premature vascular ageing of the aorta which can be measured by aortic pulse wave velocity (Ao-PWV). Endoplasmic reticulum (ER) stress is involved in the pathogenesis of DKD and vascular ageing. Klotho is a kidney derived circulating anti-ageing hormone with vasculo-protective properties.My thesis aims to explore the relationship of Ao-PWV, Klotho and the Unfolded Protein Response (UPR), a cytoprotective response to increased ER stress, with the pathophysiology and progression of DKD. I also evaluated if distinct patterns of estimated glomerular filtration rate (eGFR) trajectories are associated with progression of DKD to ESRD. The cardio-renal biomarkers I have studied may help identify people at high risk of DKD progression and cardiovascular disease.
My hypotheses were:
1. Increased levels of circulating Klotho (sKlotho) have a favourable prognostic role in DKD and diabetic retinopathy another microvascular complication of diabetes.
2. Ao-PWV is a bio-marker for DKD progression.
3. Progression of DKD to ESRD can occur in non-linear eGFR trajectories.
4. Lower level of sKlotho is associated with increased Ao-PWV
5. sKlotho may confer cardiorenal protection by ameliorating UPR in glomerular endothelial cells and improving arterial distensibility by its effect on aortic smooth muscle cells.
The key results of my thesis are summarized below:
1. A) In people with type 2 diabetes (T2DM) lower sKlotho levels at baseline was an independent predictor of > 50% fall in eGFR.
B) In people with type 1 diabetes of >20 years duration, presence of DKD was associated with lower levels of sKlotho.
C) In people with T2DM lower sKlotho levels at baseline was an independent predictor of the onset and progression of diabetic retinopathy.
2. In T2DM raised Ao-PWV predicted faster decline in eGFR independent of traditional risk factors. Majority of people with DKD who reach ESRD have a non-linear decline in eGFR with distinct trajectories associated with African-Carribean ethnicity and HbA1c variability.
3. In people with T2DM and DKD lower sKlotho levels were independently associated with increased Ao-PWV.
4. In vitro sKlotho pre-treatment ameliorates UPR response to tunicamycin induced ER stress in human glomerular endothelial cells. sKlotho exerts a protective effect in human aortic smooth muscle cells treated with angiotensin II and favours a less osteogenic phenotype. This may explain our clinical observations of the associations between low sKlotho levels, raised Ao-PWV and eGFR fall.
| Date of Award | 1 Apr 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Janaka Karalliedde (Supervisor) & Luigi Gnudi (Supervisor) |