Title: Urinary trace element profile as an early biomarker of acute kidney injury
Funder: Department of Health and Social Care

Abstract: Rationale AKI is common in hospitalised patients, confers high risk of mortality and co-morbidity but is potentially treatable if detected early. Serum creatinine (SCr) is the standard test for detecting AKI but is a poor biomarker for AKI because of significant delay in its increase. There is urgent need for a reliable early biomarker for AKI. Aim From a porcine model, we identified 2 novel early biomarkers for AKI. We aim to validate the assay in patients undergoing cardiac surgery, who are at relatively high risk of AKI. We shall then develop a point-of-care-test (POCT) to facilitate widespread bedside measurement of these urinary biomarkers. Challenge The ideal AKI biomarker would be sensitive, specific, reproducible and easy/cheap to measure. We identified urinary cadmium (Cd) and copper (Cu) as AKI biomarkers in a porcine model. We demonstrated that these elements are elevated in urine of patients with AKI but are low in urine of healthy volunteers. The challenge is to validate the assays in a clinical study then develop benchtop and handheld POCTs which can measure urinary Cd and Cu quickly and accurately. Clinical study We shall recruit patients >18 years undergoing cardiac surgery, who have one or more risk factors for AKI (age >65 years, CKD, heart failure, liver disease, peripheral vascular disease). Urine will be sampled pre-operatively and at intervals to 24 hours post-op. Aliquots will be stored at -80 degrees for ICP-MS and later POCT assays, as well as for assay of comparator biomarkers (NGAL, 'NephroCheck'). Renal outcome will be determined over 7 days post-operatively using KDIGO criteria. Primary analysis will determine whether urinary minerals predict AKI. Further analysis will determine whether biomarker levels predict AKI stage (KDIGO 1-3). For the latter, 13 patients per AKI stage will be required. Our large local AKI database allows us to predict ratio of AKI outcomes (stage 0-3) after cardiac surgery, with stage 3 occurring in approximately 5% and stage 0 (no AKI) in approximately 80% of patients. By recruiting those with multiple risk factors for AKI, we should increase observed incidence of AKI and thus increase probability of recruiting 13 per outcome-group. We shall restrict recruitment to 150 patients over 18 months (increased from 120 following discussion at interview in round 9). We shall also pool stages 2 and 3 ('moderate-severe' AKI) for analysis, to compare sensitivity and specificity with other AKI biomarkers. To test assay specificity further, we shall recruit 20 people from each of 3 other groups: healthy volunteers; patients with urinary tract infection; patients with stage 5 CKD. New Product Gold-standard for measurement of trace elements, including Cd and Cu, is inductively-coupled-plasma mass spectrometry (ICP-MS). This is not used routinely in NHS laboratories, nor could it be miniaturised as a POCT. Our partner, Trace2o, has developed portable equipment to measure trace elements, including Cd and Cu, as contaminants in water and soil. We shall develop POCT devices to quantify these elements in urine. Having validated Cd and Cu with ICP-MS in the clinical study, we shall develop two POCT devices: benchtop and handheld, each modified from existing Trace2o technology. Software and app will be developed, allowing results to be accessed by tablet devices. We shall validate the devices using stored samples from the clinical study. Schedule The project comprises 7 work packages (please see Gantt chart): project management; PPI; clinical study; assay validation; POCT design and evaluation; health economics and marketing; project review. Five milestones: 1.Protocol approvals for clinical study (month 6). 2. Completion of patient recruitment (month 24). 3.Validation of ICP-MS/POCT assays (month 27). 4. Optimisation of POCT/CE marking (month 30). 5.Completion of diagnostic kit (month 33)

Lay abstract: Acute kidney injury (AKI) is a rapid deterioration in kidney function over hours or days. It is common, occurring in 10-20% of patients admitted to hospital. AKI can be caused by serious illness, major operations, trauma or by some medicines. Most cases are mild and kidney function often improves. Some cases are severe, resulting in kidney failure and need for dialysis (a 'kidney machine'), until the kidneys improve. Occasionally kidney function does not recover, leaving the patient requiring life-long regular dialysis or a kidney transplant. AKI is very important to patients and the NHS because it is: 1. Common in patients admitted to hospital. 2. Serious. Patients with AKI: are more likely to die during their hospital stay compared with patients without AKI. stay in hospital longer. are more likely to develop long term kidney problems. 3. Expensive AKI costs the NHS more than &pound;1 billion per year. AKI is often preventable or treatable with simple measures (such as fluids, antibiotics for infection, or avoiding certain medicines) if patients at risk are identified early. At present, no good test is available for detecting the early stages of kidney damage. Kidney damage can get worse before doctors identify the problem. Kidney function is measured with a blood test called creatinine. Blood levels of creatinine increase after kidney damage, but this can take more than 24 hours. We urgently need a test that detects AKI earlier. We have identified 2 minerals in urine that increase within an hour of kidney damage. We plan to measure these minerals in urine from some patients having heart surgery, to see whether the amount of each mineral tells us whether a patient will develop AKI. We shall then develop a small kit so that the test can be done quickly on the ward.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: RENAL AND UROGENITAL