Title: Why do children with severe chronic kidney disease present late to specialist services? A mixed-methods observational study.
Funder: Department of Health and Social Care

Abstract: Background:Childhood chronic kidney disease (CKD) is a significant UK and global health problem. Progression to end-stage' kidney disease (ESKD) necessitates renal replacement therapy (RRT) as dialysis or renal transplantation. Dialysis poses a substantial burden for patients, families and the NHS.Currently in the UK, 891 children under 16 years undergo RRT across 13 centers. In 2013, 124 patients commenced RRT: an incidence of 9.3 children per million age-related population1. For children, dialysis has deleterious outcomes including poor growth, bone disease and cardiovascular morbidity2-4. Significant impairments in cognition and educational attainment correlate with dialysis duration5. Children report loss of self-esteem, identity and independence6. Furthermore, quality of life (QoL) for patients and families is impacted to accommodate the requirements of dialysis. Parents specifically must adopt a health-care provider' role: balancing home-life with complex medical regimens while managing stress, uncertainty and disruption to support networks7.For the NHS, RRT is costly; accounting for 1-2% of healthcare expenditure8. Kidney transplantation is the most cost-effective treatment for patients9, is associated with improved survival, QoL, and imposes fewer limitations on day-to-day activities. Consequently, European paediatric guidance advocates early/pre-emptive transplantation to minimize exposure to dialysis and its related morbidities10. Unfortunately, one in four UK children commencing dialysis present late' to nephrology services i.e. within three months of requiring RRT. This incidence remains unchanged over time. Strong evidence for late presentation includes age >12 years, female sex and Black, Asian and other ethnic minorities. Little is known about why this variation exists. Few studies suggest late presenters experience greater complications including significant uraemia, hypertension, fluid overload and intensive care stays11-12. Access to transplantation, particularly pre-emptive transplantation is also reduced13.Benefits to patients/NHS:If children with CKD are identified early, opportunities exist to delay/ minimize dialysis. Epidemiological studies demonstrate faster disease progression for children presenting with lower levels of renal function14-15. Additionally, aggressive treatment of parameters including hypoalbuminaemia, anaemia, blood pressure and proteinuria delays progression to ESKD16-21. Timely identification enables specialist teams to prepare patients for RRT, allowing families time to adjust to and become competent in the daily management of their child's needs22.Aims:This fellowship seeks to determine pathways to treatment for children with CKD (appendix one). It focuses on children for whom apparent inequities exist in accessing specialist care, namely late presenters. We aim to identify factors contributing to late presentation that may serve as targets for interventions to improve detection, treatment, and ultimately prognosis23-24.Key Questions: Is the likelihood of late presentation affected by demographic, clinical or geographical factors? Are there red-flag symptoms that predict CKD? Do CKD children access primary care more frequently before diagnosis? What are the care pathway experiences of families affected by late presentation? What are the perceived barriers/triggers to identification and referral of CKD for general practitioners (GPs), the gate-keepers' to specialist services25? Plan:The study uses a mixed-methods approach to determine factors implicated in late presentation. A systematic review will ascertain what is currently known. Quantitative analysis of demographic, clinical and geographical variables on likelihood of late presentation will be performed using UK Renal Registry (UKRR) data. A nested-case control study, using Clinical Practice Research Datalink (CPRD) data, will analyse patterns of primary care use prior to a CKD diagnosis. Finally semi-structured interviews with late presenter families and GPs will explore pathways to specialist care from patient and clinician perspectives. Reducing health-care variations and improving chronic disease outcomes are targets established by the WHO and RCPCH26-27. This fellowship also addresses the 2014 NIHR call for research into long-term childhood conditions28 and the 2016 World Kidney Day theme of Kidney disease in children: act early to prevent it!'29.

Lay abstract: Background: Chronic kidney disease (CKD) in childhood is a significant problem in the UK and worldwide, with long-lasting health effects. In severe or end-stage' kidney disease (ESKD) renal replacement therapy (RRT) is needed to substitute the role of the kidneys. This may be in the form of dialysis or a kidney transplant. Dialysis is a mechanical treatment that prevents the build-up of toxins and must be administered regularly. A kidney transplant provides the patient with a working kidney matched from a person known to them, or someone who has died, allowing them to return to near normal kidney function. In the UK, there are currently about 900 children requiring RRT. For children, dialysis is not a perfect treatment. It can affect their physical health, growth and development. Children report their quality of life is greatly affected. School and home-life is disrupted placing large strains on the whole family. The best treatment for children with severe CKD is a kidney transplant. The gold standard' is for transplantation before dialysis is needed (a pre-emptive' transplant). A transplant provides the best chance for normal growth and development. It is also the most cost-effective therapy for severe CKD. In an ideal world, all children with CKD would be identified early on in their condition and steps put in place to optimize their remaining kidney function. They would be prepared physically and psychologically for a transplant or dialysis, and time taken to find an ideal kidney donor. Additionally patients and their families would have time to come to terms with the diagnosis and engage with support services. Sadly, for 25% of children who end up on long-term RRT, their initial diagnosis and treatment is made late' (less than three months from their first appointment with a specialist to starting dialysis). Due to the severity of their kidney disease, they miss out on the chance for treatment to prolong kidney function, or to receive a transplant before needing dialysis. Other research suggests late presenters' are more unwell and may need intensive care. While it is inevitable that some kidney diseases will be unforeseen and progress rapidly, there are too many children currently missing out on the benefits of early detection. Over the past 25 years, we have not made any improvements in the scale of this problem. There is very little understanding of why some children present late while others with similar kidney diseases present early. However it is clear speaking to patients and families that the impact is huge. Aim: This aim is for this fellowship is to determine why some children with kidney disease are not picked up until their function is very severe. Through identifying features linked to a delay in presentation and understanding their impact we can begin to address this important problem. The objectives are to: 1. Understand what is already known about 'late presenters' through a review of the literature. 2. Understand whether disadvantaged children or those further away from a specialist centre are more likely to present late to specialist care, taking into account other factors such as their diagnosis and ethnicity. 3. Identify if there are red flag features that can predict kidney disease in children prior to diagnosis. We will look at these factors in children on dialysis (cases) and compare them to children in the general population (controls) to see if there is a difference. 4. Perform interviews of late presenter' children and their parents/carers to learn more about their experiences, the impact of late presentation, and their pathway to specialist care. 5. Perform interviews with GPs to understand how they might identify children with kidney problems, and to explore issues that may act as barriers or triggers to referral. This research question has been deemed a priority by charities including the UK Renal Registry. Improving long-term child health problems and reducing variations in care are also key objectives for the Royal College of Paediatrics and Child Health (RCPCH) and the World Health Organisation (WHO). Patient involvement and dissemination: Patients and their carers approved the research question and design. This was done through group discussions, questionnaires and charity support. We will publish all parts of this study in journals. I will report our results back to charities and patient groups and intend to keep the public up-to-date in part using social media. The findings of this research will be used to design a future intervention study, aimed at increasing the detection of children with kidney disease in a timely fashion.

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