Title: STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI): UK arm of a multi-centre randomized controlled trial
Funder: Department of Health and Social Care

Abstract: Design: UK arm of international multi-centre randomised controlled trial Setting: NHS intensive care units (ICUs) in the UK Population: Critically ill adult patients with acute kidney injury (AKI) and no immediate indication for renal replacement therapy (RRT) Inclusion criteria: i) age 18 years or older; ii) admission to ICU; iii) serum creatinine 100 µmol/L or higher in women, and 130 µmol/L or higher in men (to account for differences in baseline values between men and women); iv) AKI stage 2 or 3 Exclusion criteria: i) lack of commitment to ongoing life support (including RRT); ii) presence of a drug overdose that necessitates RRT; iii) RRT within the previous 2 months; iv) kidney transplant within the past year; v) known advanced chronic kidney disease (estimated GFR <20 mL/min/1.73 m2) pre-hospitalisation; vi) confirmed or suspected renal obstruction or primary renal disease; vii) serum potassium >5.5 mmol/L; viii) serum bicarbonate <15 mmol/L. Health technologies: Accelerated versus standard indication-driven initiation of RRT for AKI Outcomes: Primary outcome is survival at 90 days after randomisation. Secondary outcomes are important patient and renal specific outcomes (renal function, dialysis dependence, proteinuria, quality of life, death) and use of health care resource and quality of life at one year. The UK arm will determine cost-effectiveness at one year and over patients’ lifetimes. Methods: Patients randomised to the accelerated arm will be started on RRT within 12 hours of eligibility. In patients randomised to standard initiation, RRT will be discouraged until serum potassium >5.9 mmol/L, pH <7.21 or serum bicarbonate <13 mmol/L, respiratory failure due to fluid overload, or persistent AKI stage 2 or 3 for >72 hours. Renal and patient outcomes and health care resource use data will be collected at 3 months, 1 year and long-term through direct contact with the patient and their GP and linkage with the UK Renal Registry and Hospital Episode Statistics (HES) data. We will undertake a cost-utility analysis of early RRT compared to usual care from the perspective of health and social care services in the UK. This will include an analysis based on the trial data applying a 1 year time horizon and analysis applying a lifetime time horizon and extrapolating available trial and literature data in a Markov model. Data collection on resource use will include length of stay in hospital and ICU, organ support during ICU stay and data on secondary regarding the extrapolation of data. beyond 90 days. Sensitivity analyses will be undertaken to test the sensitivity of the results to structural assumptions regarding the extrapolation of data. Sample size: total sample size of main study n=2866 of whom 20% (n=580) will be recruited in the UK Timetable: June 2018: amendment of protocol and patient information sheets to include NHS specific health economics and long-term follow-up (regulatory approvals are already in place for the main trial without NHS specific health economics and long-term follow up) July - Dec 2018: activation of new sites June 2020: completion of patient recruitment May 2021: 1 year follow up of last recruited patient June 2021: linkage with UK Renal Registry and HES data Nov 2021: completion of health economic analysis and preparation of report Expertise: ICU clinicians, health economists, methodologists, patient representative, statistician, trialists

Lay abstract: Acute kidney injury (AKI) is the term used to describe sudden worsening of kidney function. It was previously called acute kidney failure. In patients with AKI, salts, waste products and fluid build up. This can harm other organs, in particular the heart and lungs. AKI can range from mild worsening of kidney function to complete kidney failure. More than half of the critically ill patients treated in a hospital Intensive Care Unit (ICU) develop AKI. They often stay in hospital for longer, have more complications and a higher risk of dying compared to patients without AKI. Most patients with AKI recover their kidney function but occasionally people are left with long-term kidney failure. It is currently not possible to know which patients with AKI will recover kidney function and who won't. In addition, people who have survived AKI remain at risk of long-term health problems even if their kidney function gets better. Patients with severe AKI often need dialysis treatment, also known as renal replacement therapy (RRT) until their kidneys recover. During RRT, toxins and excess fluid are removed and this can be life saving. However, RRT has side effects: for instance, it has to be done through a tube or catheter placed in a large vein in the neck or groin, which can be complicated by bleeding and blood stream infections. There is also a risk that patients' blood pressure may be difficult to control during RRT. Finally, RRT is expensive. At present it is not clear whether it is better to start RRT early (ie. before a lot of toxins and fluid have accumulated), or whether RRT should be avoided until it is absolutely needed. Starting RRT earlier would mean that waste products and excess fluid are removed before they build up to dangerous levels. This may benefit other organs, too and may allow patients to get better faster. The downside is that some patients will receive the treatment even though their kidneys would have recovered anyway. These patients are also at risk of complications from a treatment that they did not absolutely need. Leaving RRT until it is absolutely necessary means that RRT is avoided in patients whose kidneys will recover on their own. However, this approach has the risk that in some patients, toxins and water may build up to very high levels before RRT is started. This may affect other organs and prolong the stay in the ICU. STARRT-AKI is a research study that aims to solve the dilemma of when it is best to start RRT. Patients with AKI who don't absolutely need RRT will either receive RRT within 12 hours of being diagnosed with signs of AKI or only when toxins and excess fluid have reached a high level. The main aim is to find out whether either strategy improves the chances of people surviving and recovering their kidney function. There will be no change in any other treatments. Information including age, sex, complication rate, survival, quality of life and level of kidney function up to 1 year will be collected. In the UK, we will collect additional data, including information held on national registries such as Health Episode Statistics and the UK Renal Registry. This will enable us to investigate the effects on the patients’ health after 1 year so that we can work out the risks and benefits of the different approaches for patients in the NHS. The results will help doctors to decide when best to start RRT so that patients benefit most and the risks of RRT can be avoided without causing harm.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RENAL AND UROGENITAL