A systematic review of symptoms experienced by children and young people with kidney failure.

BACKGROUND: Kidney failure at any age has a significant impact on quality of life (QoL) but the overall symptom burden for children and young people (CYP) is poorly described. Kidney failure has no cure and whilst transplantation is the preferred management option, it is not always possible, with patients requiring supportive care at the end of their lives. AIM: To use the literature to understand the symptom burden for CYP with kidney failure who are approaching end-of-life. METHODS: Using three databases, a systematic literature review was performed to identify eligible studies to extract data on symptoms experienced in CYP aged < 21 years with kidney failure. Data extraction was completed by two authors using a pre-designed proforma. Study quality assessment was undertaken using the BMJ AXIS tool. RESULTS: A total of 20,003 titles were screened to yielding 35 eligible studies including 2,862 CYP with chronic kidney disease (CKD), of whom 1,624 (57%) had CKD stage 5. The studies included a median of 30 (range 7-241) patients. Symptoms were subcategorised into eight groups: sleep, mental health, gastrointestinal, dermatology, ear, nose and throat (ENT), neurology, multiple symptoms, and ophthalmology. The prevalences of the most commonly reported symptoms were: restless leg syndrome 16.7-45%, sleep disordered breathing 20-46%, hypersomnia 14.3-60%, depression 12.5-67%, anxiety 5.3-34%, overall gastrointestinal symptoms 43-82.6%, nausea and vomiting 15.8-68.4%, abdominal pain 10.5-67.4%, altered appetite or anorexia 19-90%, xerosis 53.5-100%, pruritis 18.6-69%, headache 24-76.2% and ophthalmological symptoms 26%. Within each subgroup, the symptom definitions used were heterogeneous, the methods of assessment were varied and some symptoms, such as pain and constipation, were poorly represented. CONCLUSIONS: There is a marked lack of evidence relating to the symptom burden for CYP with CKD. This study highlights the high symptom prevalence, particularly in relation to sleep, mental health, headache, dermatological and gastrointestinal symptoms. There is a need for consensus recommendations on the evaluation and management of symptoms for CYP with CKD approaching end-of-life. PROSPERO ID: CRD42022346120.

Protocol for a multicentre prospective exploratory mixed-methods study investigating the modifiable psychosocial variables influencing access to and outcomes after kidney transplantation in children and young people in the UK.

INTRODUCTION: Kidney transplantation is the preferred therapy for children with stage 5 chronic kidney disease (CKD-5). However, there is a wide variation in access to kidney transplantation across the UK for children. This study aims to explore the psychosocial factors that influence access to and outcomes after kidney transplantation in children in the UK using a mixed-methods prospective longitudinal design. METHODS: Qualitative data will be collected through semistructured interviews with children affected by CKD-5, their carers and paediatric renal multidisciplinary team. Recruitment for interviews will continue till data saturation. These interviews will inform the choice of existing validated questionnaires, which will be distributed to a larger national cohort of children with pretransplant CKD-5 (n=180) and their carers. Follow-up questionnaires will be sent at protocolised time points regardless of whether they receive a kidney transplant or not. Coexisting health data from hospital, UK renal registry and National Health Service Blood and Transplant registry records will be mapped to each questionnaire time point. An integrative analysis of the mixed qualitative and quantitative data will define psychosocial aspects of care for potential intervention to improve transplant access. ANALYSIS: Qualitative data will be analysed using thematic analysis. Quantitative data will be analysed using appropriate statistical methods to understand how these factors influence access to transplantation, as well as the distribution of psychosocial factors pretransplantation and post-transplantation. ETHICS AND DISSEMINATION: This study protocol has been reviewed by the National Institute for Health Research Academy and approved by the Wales Research Ethics Committee 4 (IRAS number 270493/ref: 20/WA/0285) and the Scotland A Research Ethics Committee (ref: 21/SS/0038). Results from this study will be disseminated across media platforms accessed by affected families, presented at conferences and published in peer-reviewed journals.

Identification of patients undergoing chronic kidney replacement therapy in primary and secondary care data: validation study based on OpenSAFELY and UK Renal Registry.

Objective: To validate primary and secondary care codes in electronic health records to identify people receiving chronic kidney replacement therapy based on gold standard registry data. Design: Validation study using data from OpenSAFELY and the UK Renal Registry, with the approval of NHS England. Setting: Primary and secondary care electronic health records from people registered at 45% of general practices in England on 1 January 2020, linked to data from the UK Renal Registry (UKRR) within the OpenSAFELY-TPP platform, part of the NHS England OpenSAFELY covid-19 service. Participants: 38 745 prevalent patients (recorded as receiving kidney replacement therapy on 1 January 2020 in UKRR data, or primary or secondary care data) and 10 730 incident patients (starting kidney replacement therapy during 2020), from a population of 19 million people alive and registered with a general practice in England on 1 January 2020. Main outcome measures: Sensitivity and positive predictive values of primary and secondary care code lists for identifying prevalent and incident kidney replacement therapy cohorts compared with the gold standard UKRR data on chronic kidney replacement therapy. Agreement across the data sources overall, and by treatment modality (transplantation or dialysis) and personal characteristics. Results: Primary and secondary care code lists were sensitive for identifying the UKRR prevalent cohort (91.2% (95% confidence interval (CI) 90.8% to 91.6%) and 92.0% (91.6% to 92.4%), respectively), but not the incident cohort (52.3% (50.3% to 54.3%) and 67.9% (66.1% to 69.7%)). Positive predictive values were low (77.7% (77.2% to 78.2%) for primary care data and 64.7% (64.1% to 65.3%) for secondary care data), particularly for chronic dialysis (53.7% (52.9% to 54.5%) for primary care data and 49.1% (48.0% to 50.2%) for secondary care data). Sensitivity decreased with age and index of multiple deprivation in primary care data, but the opposite was true in secondary care data. Agreement was lower in children, with 30% (295/980) featuring in all three datasets. Half (1165/2315) of the incident patients receiving dialysis in UKRR data had a kidney replacement therapy code in the primary care data within three months of the start date of the kidney replacement therapy. No codes existed whose exclusion would substantially improve the positive predictive value without a decrease in sensitivity. Conclusions: Codes used in primary and secondary care data failed to identify a small proportion of prevalent patients receiving kidney replacement therapy. Codes also identified many patients who were not recipients of chronic kidney replacement therapy in UKRR data, particularly dialysis codes. Linkage with UKRR kidney replacement therapy data facilitated more accurate identification of incident and prevalent kidney replacement therapy cohorts for research into this vulnerable population. Poor coding has implications for any patient care (including eligibility for vaccination, resourcing, and health policy responses in future pandemics) that relies on accurate reporting of kidney replacement therapy in primary and secondary care data.

Epidemiology of childhood acute kidney injury in England using e-alerts.

Background: Few studies describe the epidemiology of childhood acute kidney injury (AKI) nationally. Laboratories in England are required to issue electronic (e-)alerts for AKI based on serum creatinine changes. This study describes a national cohort of children who received an AKI alert and their clinical course. Methods: A cross-section of AKI episodes from 2017 are described. Hospital record linkage enabled description of AKI-associated hospitalizations including length of stay (LOS) and critical care requirement. Risk associations with critical care (hospitalized cohort) and 30-day mortality (total cohort) were examined using multivariable logistic regression. Results: In 2017, 7788 children (52% male, median age 4.4 years, interquartile range 0.9-11.5 years) experienced 8927 AKI episodes; 8% occurred during birth admissions. Of 5582 children with hospitalized AKI, 25% required critical care. In children experiencing an AKI episode unrelated to their birth admission, Asian ethnicity, young (<1 year) or old (16-<18 years) age (reference 1-<5 years), and high peak AKI stage had higher odds of critical care. LOS was higher with peak AKI stage, irrespective of critical care admission. Overall, 30-day mortality rate was 3% (n = 251); youngest and oldest age groups, hospital-acquired AKI, higher peak stage and critical care requirement had higher odds of death. For children experiencing AKI alerts during their birth admission, no association was seen between higher peak AKI stage and critical care admission. Conclusions: Risk associations for adverse AKI outcomes differed among children according to AKI type and whether hospitalization was related to birth. Understanding the factors driving AKI development and progression may help inform interventions to minimize morbidity.

Disparities in treatment and outcome of kidney replacement therapy in children with comorbidities: an ESPN/ERA Registry study.

Background: Data on comorbidities in children on kidney replacement therapy (KRT) are scarce. Considering their high relevance for prognosis and treatment, this study aims to analyse the prevalence and implications of comorbidities in European children on KRT. Methods: We included data from patients <20 years of age when commencing KRT from 2007 to 2017 from 22 European countries within the European Society of Paediatric Nephrology/European Renal Association Registry. Differences between patients with and without comorbidities in access to kidney transplantation (KT) and patient and graft survival were estimated using Cox regression. Results: Comorbidities were present in 33% of the 4127 children commencing KRT and the prevalence has steadily increased by 5% annually since 2007. Comorbidities were most frequent in high-income countries (43% versus 24% in low-income countries and 33% in middle-income countries). Patients with comorbidities had a lower access to transplantation {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]} and a higher risk of death [aHR 1.79 (95% CI 1.38-2.32)]. The increased mortality was only seen in dialysis patients [aHR 1.60 (95% CI 1.21-2.13)], and not after KT. For both outcomes, the impact of comorbidities was stronger in low-income countries. Graft survival was not affected by the presence of comorbidities [aHR for 5-year graft failure 1.18 (95% CI 0.84-1.65)]. Conclusions: Comorbidities have become more frequent in children on KRT and reduce their access to transplantation and survival, especially when remaining on dialysis. KT should be considered as an option in all paediatric KRT patients and efforts should be made to identify modifiable barriers to KT for children with comorbidities.

Understanding the perspectives of recruiters is key to improving randomised controlled trial enrolment: a qualitative evidence synthesis.

BACKGROUND: Recruiting patients to randomised controlled trials (RCTs) is often reported to be challenging, and the evidence base for effective interventions that could be used by staff (recruiters) undertaking recruitment is lacking. Although the experiences and perspectives of recruiters have been widely reported, an evidence synthesis is required in order to inform the development of future interventions. This paper aims to address this by systematically searching and synthesising the evidence on recruiters' perspectives and experiences of recruiting patients into RCTs.  METHODS: A qualitative evidence synthesis (QES) following Thomas and Harden's approach to thematic synthesis was conducted. The Ovid MEDLINE, CINAHL, EMBASE, PsycInfo, Cochrane Central Register of Controlled Trials, ORRCA and Web of Science electronic databases were searched. Studies were sampled to ensure that the focus of the research was aligned with the phenomena of interest of the QES, their methodological relevance to the QES question, and to include variation across the clinical areas of the studies. The GRADE CERQual framework was used to assess confidence in the review findings. RESULTS: In total, 9316 studies were identified for screening, which resulted in 128 eligible papers. The application of the QES sampling strategy resulted in 30 papers being included in the final analysis. Five overlapping themes were identified which highlighted the complex manner in which recruiters experience RCT recruitment: (1) recruiting to RCTs in a clinical environment, (2) enthusiasm for the RCT, (3) making judgements about whether to approach a patient, (4) communication challenges, (5) interplay between recruiter and professional roles. CONCLUSIONS: This QES identified factors which contribute to the complexities that recruiters can face in day-to-day clinical settings, and the influence recruiters and non-recruiting healthcare professionals have on opportunities afforded to patients for RCT participation. It has reinforced the importance of considering the clinical setting in its entirety when planning future RCTs and indicated the need to better normalise and support research if it is to become part of day-to-day practice. TRIAL REGISTRATION: PROSPERO CRD42020141297 (registered 11/02/2020).

Advanced chronic kidney disease among UK children.

The UK Renal Registry currently collects information on UK children with kidney failure requiring long-term kidney replacement therapy (KRT), which supports disease surveillance and auditing of care and outcomes; however, data are limited on children with chronic kidney disease (CKD) not on KRT. METHODS: In March 2020, all UK Paediatric Nephrology centres submitted data on children aged <16 years with severely reduced kidney function as of December 2019, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m2. RESULTS: In total, 1031 children had severe CKD, the majority of whom (80.7%) were on KRT. The overall prevalence was 81.2 (95% CI 76.3 to 86.3) per million of the age-related population. CONCLUSIONS: The prevalence of severe CKD among UK children is largely due to a high proportion of children on long-term KRT. Expanding data capture to include children with CKD before reaching failure will provide greater understanding of the CKD burden in childhood.

Mixed-methods research in nephrology.

Mixed-methods research involves the mixing of at least 1 qualitative and 1 quantitative method in the same research project or set of related projects. Combined use of qualitative and quantitative research methods in nephrology has increased over the last 10 years. In this review, we aim to advance the understanding of mixed-methods research within the kidney community. Qualitative and quantitative techniques provide different but noncompeting representations of what exists in the world; findings from qualitative research do not generalize to a large population, whereas those from quantitative research may not apply to individuals within the diverse and heterogeneous larger population. Mixed-methods research combines these complementary representations, allowing the strengths of each method to be combined and the strengths of 1 method to address the limitations of the other. Mixed-methods approaches can be used to: (i) gain a more complete understanding of a research problem, (ii) explain initial results from one method with results from another, (iii) generate instruments, for example, survey tools and interventions, (iv) evaluate services, and (v) optimize clinical trial design and delivery. There are 3 core mixed-methods designs: explanatory sequential, exploratory sequential, and convergent parallel, which can be combined. We discuss each design in turn before discussing analysis and integration of findings from the different methods. We provide case studies that illustrate the application of these study designs to kidney research questions. We briefly discuss mixed-methods systematic reviews and evidence synthesis before finally highlighting guidance on how to appraise published mixed-methods research.

Increasing trends in hemodialysis and living donor kidney transplantation for children and young people in the United Kingdom.

BACKGROUND: The UK Renal Registry is responsible for the national collection and reporting of data on all children receiving long-term kidney replacement therapy [KRT], including kidney transplantation. METHODS: All 13 UK pediatric nephrology centers contributed to providing individual patient data from the pediatric population incident to and prevalent to KRT as per the date 31 December 2018. Data for children aged 16-<18 years were presented separately as some were managed under adult care settings with different methods of data collection. Demographics and biochemical data, including kidney function and prevalence of cardiovascular risk factors [hypertension, hypercholesterolemia, BMI] were reported. RESULTS: Eight hundred and twenty-six children (65.4 per million age-related population [pmarp]) and 199 young people (139.4pmarp) in the United Kingdom were prevalent to KRT on 31 December 2018. Overall, the incidence of KRT during 2018 was 9.1 pmarp and 12.6 pmarp in children and young people, respectively. Congenital anomalies of the kidney and urinary tract (CAKUT) were the most prevalent primary diagnoses (52%). Living and deceased donor transplantation was the most common treatment modality (78%). Patients on dialysis had lower age standardized mean height and weight ranges recorded in comparison to transplant patients [median height z score -1.8 vs. -1.1]. 73.1% patients had one or more cardiovascular disease risk factors. CONCLUSIONS: This study highlights increasing prevalence of hemodialysis and living donor transplantation as modalities for KRT. Of those incident to KRT, the highest patient survival was seen among 8-12 years and lowest <2 years. Moreover, there was a demographic shift from Caucasian toward Asian/other ethnicity and from CAKUT to other primary kidney diseases.

Acute kidney injury identification for pharmacoepidemiologic studies: Use of laboratory electronic acute kidney injury alerts versus electronic health records in Hospital Episode Statistics.

PURPOSE: A laboratory-based acute kidney injury (AKI) electronic-alert (e-alert) system, with e-alerts sent to the UK Renal Registry (UKRR) and collated in a master patient index (MPI), has recently been implemented in England. The aim of this study was to determine the degree of correspondence between the UKRR-MPI and AKI International Classification Disease-10 (ICD-10) N17 coding in Hospital Episode Statistics (HES) and whether hospital N17 coding correlated with 30-day mortality and emergency re-admission after AKI. METHODS: AKI e-alerts in people aged ≥18 years, collated in the UKRR-MPI during 2017, were linked to HES data to identify a hospitalised AKI population. Multivariable logistic regression was used to analyse associations between absence/presence of N17 codes and clinicodemographic features. Correlation of the percentage coded with N17 and 30-day mortality and emergency re-admission after AKI were calculated at hospital level. RESULTS: In 2017, there were 301 540 adult episodes of hospitalised AKI in England. AKI severity was positively associated with coding in HES, with a high degree of inter-hospital variability-AKI stage 1 mean of 48.2% [SD 14.0], versus AKI stage 3 mean of 83.3% [SD 7.3]. N17 coding in HES depended on demographic features, especially age (18-29 years vs. ≥85 years OR 0.22, 95% CI 0.21-0.23), as well as sex and ethnicity. There was no evidence of association between the proportion of episodes coded for AKI with short-term AKI outcomes. CONCLUSION: Coding of AKI in HES is influenced by many factors that result in an underestimation of AKI. Using e-alerts to triangulate the true incidence of AKI could provide a better understanding of the factors that affect hospital coding, potentially leading to improved coding, patient care and pharmacoepidemiologic research.

Associations between Deprivation, Geographic Location, and Access to Pediatric Kidney Care in the United Kingdom.

BACKGROUND AND OBJECTIVES: Pre-emptive kidney transplantation is advocated as best practice for children with kidney failure who are transplant eligible; however, it is limited by late presentation. We aimed to determine whether socioeconomic deprivation and/or geographic location (distance to the center and rural/urban residence) are associated with late presentation, and to what degree these factors could explain differences in accessing pre-emptive transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cohort study using prospectively collected United Kingdom Renal Registry and National Health Service Blood and Transplant data from January 1, 1996 to December 31, 2016 was performed. We included children aged >3 months to ≤16 years at the start of KRT. Multivariable logistic regression models were used to determine associations between the above exposures and our outcomes: late presentation (defined as starting KRT within 90 days of first nephrology review) and pre-emptive transplantation, with a priori specified covariates. RESULTS: Analysis was performed on 2160 children (41% females), with a median age of 3.8 years (interquartile range, 0.2-9.9 years) at first nephrology review. Excluding missing data, 478 were late presenters (24%); 565 (26%) underwent pre-emptive transplantation, none of whom were late presenting. No association was seen between distance or socioeconomic deprivation with late presentation, in crude or adjusted analyses. Excluding late presenters, greater area affluence was associated with higher odds of pre-emptive transplantation, (odds ratio, 1.20 per quintile greater affluence; 95% confidence interval, 1.10 to 1.31), with children of South Asian (odds ratio, 0.52; 95% confidence interval, 0.36 to 0.76) or Black ethnicity (odds ratio, 0.31; 95% confidence interval, 0.12 to 0.80) less likely to receive one. A longer distance to the center was associated with pre-emptive transplantation on crude analyses; however, this relationship was attenuated (odds ratio, 1.02 per 10 km; 95% confidence interval, 0.99 to 1.05) in the multivariable model. CONCLUSIONS: Socioeconomic deprivation or geographic location are not associated with late presentation in children in the United Kingdom. Geographic location was not independently associated with pre-emptive transplantation; however, children from more affluent areas were more likely to receive a pre-emptive transplant.

The incidence of and risk factors for late presentation of childhood chronic kidney disease: A systematic review and meta-analysis.

BACKGROUND: When detected early, inexpensive measures can slow chronic kidney disease progression to kidney failure which, for children, confers significant morbidity and impacts growth and development. Our objective was to determine the incidence of late presentation of childhood chronic kidney disease and its associated risk factors. METHODS: We searched MEDLINE, Embase, PubMed, Web of Science, Cochrane Library and CINAHL, grey literature and registry websites for observational data describing children <21 years presenting to nephrology services, with reference to late presentation (or synonyms thereof). Independent second review of eligibility, data extraction, and risk of bias was undertaken. Meta-analysis was used to generate pooled proportions for late presentation by definition and investigate risk factors. Meta-regression was undertaken to explore heterogeneity. RESULTS: Forty-five sources containing data from 30 countries were included, comprising 19,339 children. Most studies (37, n = 15,772) described children first presenting in kidney failure as a proportion of the chronic kidney disease population (mean proportion 0.43, 95% CI 0.34-0.54). Using this definition, the median incidence was 2.1 (IQR 0.9-3.9) per million age-related population. Risk associations included non-congenital disease and older age. Studies of hospitalised patients, or from low- or middle-income countries, that had older study populations than high-income countries, had higher proportions of late presentation. CONCLUSIONS: Late presentation is a global problem among children with chronic kidney disease, with higher proportions seen in studies of hospitalised children or from low/middle-income countries. Children presenting late are older and more likely to have non-congenital kidney disease than timely presenting children. A consensus definition is important to further our understanding and local populations should identify modifiable barriers beyond age and disease to improve access to care.

Associations with kidney transplant survival and eGFR decline in children and young adults in the United Kingdom: a retrospective cohort study.

BACKGROUND: Although young adulthood is associated with transplant loss, many studies do not examine eGFR decline. We aimed to establish clinical risk factors to identify where early intervention might prevent subsequent adverse transplant outcomes. METHODS: Retrospective cohort study using UK Renal Registry and UK Transplant Registry data, including patients aged < 30 years transplanted 1998-2014. Associations with death-censored graft failure were investigated with multivariable Cox proportional hazards. Multivariable linear regression was used to establish associations with eGFR slope gradients calculated over the last 5 years of observation per individual. RESULTS: The cohort (n = 5121, of whom n = 371 received another transplant) was 61% male, 80% White and 36% had structural disease. Live donation occurred in 48%. There were 1371 graft failures and 145 deaths with a functioning graft over a 39,541-year risk period. Median follow-up was 7 years. Fifteen-year graft survival was 60.2% (95% CI 58.1, 62.3). Risk associations observed in both graft loss and eGFR decline analyses included female sex, glomerular diseases, Black ethnicity and young adulthood (15-19-year and 20-24-year age groups, compared to 25-29 years). A higher initial eGFR was associated with less risk of graft loss but faster eGFR decline. For each additional 10 mL/min/1.73m2 initial eGFR, the hazard ratio for graft loss was 0.82 (95% CI 0.79, 0.86), p < 0.0001. However, compared to < 60 mL/min/1.73m2, higher initial eGFR was associated with faster eGFR decline (> 90 mL/min/1.73m2; - 3.55 mL/min/1.73m2/year (95% CI -4.37, - 2.72), p < 0.0001). CONCLUSIONS: In conclusion, young adulthood is a key risk factor for transplant loss and eGFR decline for UK children and young adults. This study has an extended follow-up period and confirms common risk associations for graft loss and eGFR decline, including female sex, Black ethnicity and glomerular diseases. A higher initial eGFR was associated with less risk of graft loss but faster rate of eGFR decline. Identification of children at risk of faster rate of eGFR decline may enable early intervention to prolong graft survival.

Sociodemographic features and mortality of individuals on haemodialysis treatment who test positive for SARS-CoV-2: A UK Renal Registry data analysis.

Kidney disease is a recognised risk factor for poor COVID-19 outcomes. Up to 30 June 2020, the UK Renal Registry (UKRR) collected data for 2,385 in-centre haemodialysis (ICHD) patients with COVID-19 in England and Wales. Overall unadjusted survival at 1 week after date of positive COVID-19 test was 87.5% (95% CI 86.1-88.8%); mortality increased with age, treatment vintage and there was borderline evidence of Asian ethnicity (HR 1.16, 95% CI 0.94-1.44) being associated with higher mortality. Compared to the general population, the relative risk of mortality for ICHD patients with COVID-19 was 45.4 and highest in younger adults. This retrospective cohort study based on UKRR data supports efforts to protect this vulnerable patient group.