Local membrane versus systemic consequences of peritoneal dialysis treatment

The primary intent of this thesis is to delineate the relative roles of local membrane and systemic consequences of peritoneal dialysis therapy, with particular reference to the role of inflammation and a severe, uncommon complication, encapsulating peritoneal sclerosis (EPS). Data sources comprised observational cohort studies as well as registry data: the Stoke PD study, a single centre study with clinical data, the Global Fluid Study (GFS), a multinational study with clinical data and repeated dialysate and plasma samples, and Scottish Renal Registry (SRR) and AnzData registry data. Through a cross sectional analysis of dialysate and plasma samples from GFS for inflammatory cytokines, we demonstrated that peritoneal and systemic inflammation are mostly separate processes although there is an association for IL-6 along with a steep concentration gradient from dialysate to plasma. Peritoneal inflammation, though IL-6, is the strongest determinant of peritoneal solute transport, and systemic inflammation, though IL-6, is a strong predictor of patient survival although peritoneal may contribute to systemic inflammation. Through a nested case control study of GFS we showed that inflammatory cytokines are upregulated within the peritoneum prior to developing EPS. With a nested case control design from the Stoke PD study, we showed that a decrease in ultrafiltration, likely due to increased fibrosis causing a reduction in osmotic conductance to glucose, also predisposes to EPS. A competing risks analysis of SRR and AnzData showed that patients at a high risk of death, have a low risk of EPS. These findings provide supporting evidence for the theory that the risk of EPS develops through the accumulation of inflammation-driven fibrosis due to dialysate exposure over a long period of time. Dialysate contains high concentrations of glucose and absorption of this drives impairment of systemic glucose metabolism, demonstrated through a cross sectional analysis of GFS

An update on absolute and relative indications for dialysis treatment modalities

Background Choosing a dialysis modality is an important decision for people to make as their kidney failure progresses. In doing so, their options should be informed by any absolute or relative indications that may favour one modality over another. Methods In creating this update, we reviewed literature using a framework that considered first, high-level outcomes (survival and modality transition) from large registry data and cohort studies when considering optimal patient pathways; second, factors at a dialysis provider level that might affect relative indications; and third, specific patient-level factors. Both main types of dialysis modality, peritoneal (PD) and haemodialysis (HD), and their subtypes were considered. Results For most people starting dialysis, survival is independent of modality, including those with diabetes. Better survival is seen in those with less comorbidity starting with PD or home HD, reflecting continued improvements over recent decades that have been greater than improvements seen for centre HD. There are provider-level differences in the perceived relative indications for home dialysis that appear to reflect variability in experience, prejudice, enthusiasm, and support for patients and carers. Absolute contraindications are uncommon and, in most cases, where modality prejudice exists, e.g. obesity, Adult Polycystic Kidney Disease, and social factors, this is not supported by reported outcomes. Conclusion Absolute contraindications to a particular dialysis modality are rare. Relative indications for or against particular modalities should be considered but are rarely more important than patient preferences

Centre variation in home dialysis uptake: A survey of kidney centre practice in relation to home dialysis organisation and delivery in England

Background: Disparities in home dialysis uptake across England suggest inequity and unexplained variation in access. We surveyed staff at all English kidney centres to identify patterns in service organisation/delivery and explore correlations with home therapy uptake, as part of a larger study (‘Inter-CEPt’), which aims to identify potentially modifiable factors to address observed variations. Methods: Between June and September 2022, staff working at English kidney centres were surveyed and individual responses combined into one centre-level response per question using predetermined data aggregation rules. Descriptive analysis described centre practices and their correlation with home dialysis uptake (proportion of new home dialysis starters) using 2019 UK Renal Registry 12-month home dialysis incidence data. Results: In total, 180 responses were received (50/51 centres, 98.0%). Despite varied organisation of home dialysis services, most components of service delivery and practice had minimal or weak correlations with home dialysis uptake apart from offering assisted peritoneal dialysis and ‘promoting flexible decision-making about dialysis modality’. Moderate to strong correlations were identified between home dialysis uptake and centres reporting supportive clinical leadership (correlation 0.32, 95% Confidence Interval (CI): 0.05–0.55), an organisational culture that values trying new initiatives (0.57, 95% CI: 0.34–0.73); support for reflective practice (0.38, 95% CI: 0.11–0.60), facilitating research engagement (0.39, 95% CI: 0.13–0.61) and promoting continuous quality improvement (0.29, 95% CI: 0.01–0.53). Conclusions: Uptake of home dialysis is likely to be driven by organisational culture, leadership and staff attitudes, which provide a supportive clinical environment within which specific components of service organisation and delivery can be effective

Impact of the implementation of an assisted peritoneal dialysis service on peritoneal dialysis initiation

Abstract Background There is limited information available on the impact that provision of an assisted peritoneal dialysis (PD) service has on the initiation of PD. The aim of this study was to assess this impact in a centre following initiation of assisted PD in 2011. Methods This retrospective, single-centre study analysed 1576 patients incident to renal replacement therapies (RRTs) between January 2002 and 2017. Adjusted Cox regression with a time-varying explanatory variable and a Fine and Gray model were used to examine the effect of assisted PD use on the rates and cumulative incidence of PD initiation, accounting for the non-linear impact of RRT starting time and the competing risks (transplant and death). Results Patients starting PD with assistance were older than those starting unassisted: median (interquartile range): 70.0 (61.5–78.3) versus 58.7 (43.8–69.2) years old, respectively. In the adjusted analysis assisted PD service availability was associated with an increased rate of PD initiation [cause-specific hazard ratio (cs-HR) 1.78, 95% confidence interval 1.21–2.61]. During the study period, the rate of starting PD fell before flattening out. Transplantation and death rates increased over time but this did not affect the fall in PD initiation [for each year in the study cs-HR of starting PD 0.95 (0.93–0.98), sub-distribution HR 0.95 (0.94–0.97)]. Conclusions In a single-centre study, introducing an assisted PD service significantly increased the rate of PD initiation, benefitting older patients most. This offsets a fall in PD usage over time, which was not explained by changes in transplantation or death. </jats:sec

Intervening to eliminate the centre-effect variation in home dialysis use: protocol for Inter-CEPt - a sequential mixed-methods study designing an intervention bundle

Introduction: Use of home dialysis by centres in the UK varies considerably and is decreasing despite attempts to encourage greater use. Knowing what drives this unwarranted variation requires in-depth understanding of centre cultural and organisational factors and how these relate to quantifiable centre performance, accounting for competing treatment options. This knowledge will be used to identify components of a practical and feasible intervention bundle ensuring this is realistic and cost-effective. Methods and analysis: Underpinned by the non-adoption, abandonment, scale-up, spread and sustainability framework, our research will use an exploratory sequential mixed-methods approach. Insights from multisited focused team ethnographic and qualitative research at four case study sites will inform development of a national survey of 52 centres. Survey results, linked to patient-level data from the UK Renal Registry, will populate a causal graph describing patient and centre-level factors, leading to uptake of home dialysis and multistate models incorporating patient-level treatment modality history and mortality. This will inform a contemporary economic evaluation of modality cost-effectiveness that will quantify how modification of factors facilitating home dialysis, identified from the ethnography and survey, might yield the greatest improvements in costs, quality of life and numbers on home therapies. Selected from these factors, using the capability, opportunity and motivation for behaviour change framework (COM-B) for intervention design, the optimal intervention bundle will be developed through workshops with patients and healthcare professionals to ensure acceptability and feasibility. Patient and public engagement and involvement is embedded throughout the project. Ethics and dissemination: Ethics approval has been granted by the Health Research Authority reference 20-WA-0249. The intervention bundle will comprise components for all stake holder groups: commissioners, provider units, recipients of dialysis, their caregivers and families. To reache all these groups, a variety of knowledge exchange methods will be used: short guides, infographics, case studies, National Institute for Health and Care Excellence guidelines, patient conferences, ‘Getting it Right First Time’ initiative, Clinical Reference Group (dialysis)

Peritoneal Protein Clearance Is a Function of Local Inflammation and Membrane Area Whereas Systemic Inflammation and Comorbidity Predict Survival of Incident Peritoneal Dialysis Patients

It is not clear whether the association of increased peritoneal protein clearance (PPCl) with worse survival on peritoneal dialysis (PD) is a consequence of either local or systemic inflammation or indicative of generalized endothelial dysfunction associated with comorbidity. To investigate this we determined the relationship of PPCl to comorbidity, membrane area (equivalent to low molecular weight peritoneal solute transport rate), local and systemic inflammation and hypoalbuminaemia, and for each of these with patient survival. 257 incident patients from three GLOBAL Fluid Study centers were included in this analysis. Clinical profiles were collected at baseline along with a peritoneal equilibration test, 24-h dialysate protein and paired plasma and dialysate cytokine measurements. Although peritoneal protein clearance was associated with increased age and severe comorbidity on univariate analysis, only dialysate IL-6, peritoneal solute transport rate, plasma albumin and cardiac comorbidities (ischaemic heart disease and left ventricular dysfunction) were independent explanatory variables on multivariate analysis. While peritoneal protein clearance and daily peritoneal protein loss were associated with survival in univariate analysis, on multivariate analysis only plasma IL-6, age, residual kidney function, comorbidity, and plasma albumin were independent predictors. Peritoneal protein clearance is primarily a function of peritoneal membrane area and local membrane inflammation. The association with comorbidity and survival is predominantly explained by its inverse relationship to hypoalbuminaemia, especially in diabetics

Estimating the association between systemic Interleukin-6 and mortality in the dialysis population. Re-analysis of the global fluid study, systematic review and meta-analysis

Background: Systemic inflammation, measured as circulating Interleukin-6 (IL-6) levels, is associated with cardiovascular and all-cause mortality in chronic kidney disease. However, this has not been convincingly demonstrated in a systematic review or a meta-analysis in the dialysis population. We provide such evidence, including a re-analysis of the GLOBAL Fluid Study.Methods: Mortality in the GLOBAL fluid study was re-analysed using Cox proportional hazards regression with IL-6 levels as a covariate using a continuous non-logarithmic scale. Literature searches of the association of IL-6 levels with mortality were conducted on MEDLINE, EMBASE, PyschINFO and CENTRAL. All studies were assessed for risk of bias using the QUIPS tool. To calculate a pooled effect size, studies were grouped by use of IL-6 scale and included in the meta-analysis if IL-6 was analysed as a continuous linear covariate, either per unit or per 10 pg/ml, in both unadjusted or adjusted for other patient characteristics (e.g. age, comorbidity) models. Funnel plot was used to identify potential publication bias. Results: Of 1886 citations identified from the electronic search, 60 were included in the qualitative analyses, and 12 had sufficient information to proceed to meta-analysis after full paper screening. Random effects meta-analysis of 11 articles yielded a pooled hazard ratio (HR) per pg/ml of 1.03, (95% CI 1.01, 1.03), = 81%. When the analysis was confined to seven articles reporting a non-adjusted HR the result was similar: 1.03, per pg/ml (95% CI: 1.03, 1.06), =92%. Most of the heterogeneity could be attributed to three of the included studies. Publication bias could not be determined due to the limited number of studies.Conclusion: This systematic review confirms the adverse association between systemic IL-6 levels and survival in people treated with dialysis. The heterogeneity that we observed may reflect differences in study case mix. Systematic Review Registration: PROSPERO - CRD42020214198

Centre variation in home dialysis uptake: A survey of kidney centre practice in relation to home dialysis organisation and delivery in England

Background: Disparities in home dialysis uptake across England suggest inequity and unexplained variation in access. We surveyed staff at all English kidney centres to identify patterns in service organisation/delivery and explore correlations with home therapy uptake, as part of a larger study (‘Inter-CEPt’), which aims to identify potentially modifiable factors to address observed variations. Methods: Between June and September 2022, staff working at English kidney centres were surveyed and individual responses combined into one centre-level response per question using predetermined data aggregation rules. Descriptive analysis described centre practices and their correlation with home dialysis uptake (proportion of new home dialysis starters) using 2019 UK Renal Registry 12-month home dialysis incidence data. Results: In total, 180 responses were received (50/51 centres, 98.0%). Despite varied organisation of home dialysis services, most components of service delivery and practice had minimal or weak correlations with home dialysis uptake apart from offering assisted peritoneal dialysis and ‘promoting flexible decision-making about dialysis modality’. Moderate to strong correlations were identified between home dialysis uptake and centres reporting supportive clinical leadership (correlation 0.32, 95% Confidence Interval (CI): 0.05–0.55), an organisational culture that values trying new initiatives (0.57, 95% CI: 0.34–0.73); support for reflective practice (0.38, 95% CI: 0.11–0.60), facilitating research engagement (0.39, 95% CI: 0.13–0.61) and promoting continuous quality improvement (0.29, 95% CI: 0.01–0.53). Conclusions: Uptake of home dialysis is likely to be driven by organisational culture, leadership and staff attitudes, which provide a supportive clinical environment within which specific components of service organisation and delivery can be effective

The longitudinal relationship between emotion awareness and internalising symptoms during late childhood

Emotion awareness, the ability to reflect upon the own emotions, is assumed to contribute to better mental health. However, empirical support for this relationship has only been cross-sectional. In this study we examined the extent to which individual differences in changes in emotion awareness over time can explain individual differences in changes in symptoms of internalising problems (depression, fear, worrying and ruminative thoughts). Children and young teenagers (368 boys and 295 girls) were asked four times to fill out self-report questionnaires, with a 6-month time interval between each time. The mean age was 10 years during the first data collection. Longitudinal multilevel analyses showed that the variance in emotion awareness trends was highly predictive for the variance in trends for internalizing problems over time. The ability to differentiate discrete emotions was a strong predictor and negatively contributed to all internalising symptoms. In addition, a diminished tendency to address and value emotions contributed to more depressive symptoms; whereas hiding the own emotions contributed to more worrying and ruminative thoughts. The outcomes show that individual differences in emotion awareness over time make a strong, and, above all, negative contribution to the prediction of the individual differences in various internalizing symptoms. The fact that several aspects of emotional (dys)functioning are uniquely related to different kinds of internalizing problems gives valuable and useful information not only theoretically but also clinically about the distinctive nature of these problems