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Allen, Jennifer (2020) An investigation of urinary trace elements as biomarkers for acute kidney injury. PhD thesis, University of Nottingham.

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Abstract

Acute kidney injury (AKI) is a rapid deterioration in kidney function over hours to days. It is common, affecting 10-20% of all hospital admissions, and can lead to increased mortality, lengthened hospital stay, chronic kidney disease and dialysis dependence.

AKI is identified using serum creatinine (SCr) and urine output. These are recognised to be poor and late markers of AKI; with SCr rising 24-48 hours after injury occurs. A need exists for a biomarker to enable earlier detection of AKI in order to allow early interventions and improve patient outcomes. Several existing biomarkers have attempted to fulfil this role, but all have limitations which preclude their generalised use.

From a porcine model of ischaemia reperfusion injury (IRI) and AKI, we identified that urinary cadmium (Cd) and copper (Cu) represent early markers of acute tubular injury and are promising putative biomarkers of AKI.

We performed an observational study of four patient groups at high risk of developing AKI due to IRI. Patients undergoing cardiac surgery (n=151), coronary angiography (n=40), admitted to intensive care unit (ICU) (n=150) and undergoing renal transplantation (n=150) were recruited with timed urine samples taken before and after the time of presumed IRI. Urinary trace elements (particularly Cd and Cu) were measured using inductively coupled plasma mass spectrometry (ICP-MS). AKI diagnosis was assessed using SCr and urine output.

Following cardiac surgery, incidence of AKI stage 2-3 was 8%. We demonstrated an association between an early rise in urinary Cd and Cu and the development of severe AKI. Statistical analysis did not show that urinary Cd and Cu were able to predict AKI in this group, with AUROC of 0.57 (0.48-0.65) and 0.5 (0.38-0.63) respectively. Urinary Cd and Cu had extremely high NPV in this group (93% and 95% respectively). In our pilot study of 40 patients undergoing coronary angiography incidence of AKI was 13%, with only 1 patient with AKI stage 2-3. Trends of increased urinary Cd and Cu in patients with AKI following coronary angiography were observed, but the low incidence of AKI meant that statistical significance could not be demonstrated. Incidence of AKI in ICU was lower than expected at 32%. Urinary Cd showed good predictability for AKI stage 1-3, with an AUROC of 0.71 (0.67-0.75) for the first 4 hours following admission to ICU. Urinary Cu was able to predict development of AKI modestly well, with an AUROC of 0.66 (0.63-0.69). Urinary Cu had excellent sensitivity of 81% and a high NPV of 84%. Slow and delayed graft function (SGF/DGF) were common after renal transplantation with a combined incidence of 65%. Immediately after renal transplantation urinary Cd and Cu rose significantly in all patients, and were able to predict SGF/DGF with AUROC of 0.64 (0.59-0.68) and 0.71 (0.67-0.75) respectively. Urinary Cd and Cu were better at predicting SGF/DGF than histological ATI proven on biopsy. Post hoc analyses of our study data highlighted significant problems with the current methods of detecting and staging AKI, and that there was a large variation in incidence of AKI depending on which interpretation of KDIGO urine output criteria was applied.

Results showed that urinary Cd and Cu can rise in different clinical settings soon after IRI, with higher levels seen in settings where there is prolonged or recurrent IRI. We have demonstrated a correlation between raised urinary Cd and Cu and AKI or reduced transplant function. Urinary Cd and Cu are promising early biomarkers of AKI.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Gardner, David S Devonald, Mark A
Keywords:	acute kidney injury urine biomarker
Subjects:	W Medicine and related subjects (NLM Classification) > WJ Urogenital system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	60620
Depositing User:	Gardner, David
Date Deposited:	17 Jul 2020 04:40
Last Modified:	17 Jul 2022 04:30
URI:	https://eprints.nottingham.ac.uk/id/eprint/60620

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