Biomarkers associated with AKI and CKD and their progression

Acute kidney injury (AKI) is the abrupt loss of kidney function and chronic kidney disease (CKD) is the long-term permanent reduction in kidney function; both conditions increase risk of poor outcomes for patients. AKI progression and rapid CKD progression add further increased risk of patient morbidity and mortality. Clinical biomarkers including serum creatinine (sCr), eGFR and urine output do not allow for early diagnosis and cannot predict risk of progression in AKI or CKD patients. This PhD investigated biomarkers that are associated with AKI and CKD diagnosis yet not used in clinical practice, to evaluate their utility for earlier diagnosis and to stratify patients at higher progression risk. Furthermore, this PhD used biomarker exploration tools to identify novel biomarkers associated with AKI and CKD and evaluate their ability to stratify patients based on risk of progression. In addition, due to recent research identifying a role of cellular senescence in AKI and CKD development and progression, the role of senescence in these conditions was investigated. Clinically, ECR records showed AKI (n= 57) and CKD (n= 171) patients often have numerous co-morbidities and to be prescribed numerous medications, highlighting the complexity of managing these conditions. Comparing clinical biochemical data of AKI and CKD patients to control cohorts, showed that clinical kidney function biomarkers were increased in both AKI and CKD cohorts. When clinical biomarkers were assessed for their ability to stratify patients at greater risk of progression, no single or combination of biomarkers was found useful. Analysis of biomarkers already associated with AKI and CKD was conducted using biochip array technology. Results showed that these biomarkers are capable of identifying AKI and CKD patients from controls and may be capable of early diagnosis, with novel combinations of these biomarkers identified in this thesis showing high levels of accuracy. No single or combination of these biomarkers however was able to stratify patients based on progression risk. Biomarker exploration using proximity extension assay identified novel protein signatures for AKI and CKD. Proteins CKAP4 (p < 0.0001), PTX3 (p < 0.0001) and IL-6 (p < 0.0001) were most upregulated in AKI patients compared to controls and TM (p < 0.0001), IL-2 (p < 0.0001) and CKAP4 (p< 0.0001) were most upregulated in CKD patients compared to controls. Additional analysis demonstrated that these novel biomarkers were able to stratify AKI and CKD patients at greater risk of progression. PTX3 (p < 0.01), GCSF (p < 0.01) and PSG1 (p < 0.05) were most upregulated in AKI patients at higher progression risk, and SMPD1 (p < 0.01), ADA (p < 0.01) and EGFR (p< 0.05) were most upregulated in CKD patients at risk of rapid progression. Although not as accurate as using all novel proteins from biomarker exploration, cellular senescence proteins alone were also able to differentiate AKI and CKD patients from controls and identify those at higher risk of progression, demonstrating the potential for future analysis of these proteins. The findings of this thesis have identified proteins that offer potential for improving AKI and CKD management in diagnosis and prognosis, and gives direction for future AKI and CKD research.