Managing the symptom burden associated with maintenance dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Individuals with kidney failure undergoing maintenance dialysis frequently report a high symptom burden that can interfere with functioning and diminish life satisfaction. Until recently, the focus of nephrology care for dialysis patients has been related primarily to numerical targets for laboratory measures, and outcomes such as cardiovascular disease and mortality. Routine symptom assessment is not universal or standardized in dialysis care. Even when symptoms are identified, treatment options are limited and are initiated infrequently, in part because of a paucity of evidence in the dialysis population and the complexities of medication interactions in kidney failure. In May of 2022, Kidney Disease: Improving Global Outcomes (KDIGO) held a Controversies Conference-Symptom-Based Complications in Dialysis-to identify the optimal means for diagnosing and managing symptom-based complications in patients undergoing maintenance dialysis. Participants included patients, physicians, behavioral therapists, nurses, pharmacists, and clinical researchers. They outlined foundational principles and consensus points related to identifying and addressing symptoms experienced by patients undergoing dialysis and described gaps in the knowledge base and priorities for research. Healthcare delivery and education systems have a responsibility to provide individualized symptom assessment and management. Nephrology teams should take the lead in symptom management, although this does not necessarily mean taking ownership of all aspects of care. Even when options for clinical response are limited, clinicians should focus on acknowledging, prioritizing, and managing symptoms that are most important to individual patients. A recognized factor in the initiation and implementation of improvements in symptom assessment and management is that they will be based on locally existing needs and resources.

Bio-impedance spectroscopy added to a fluid management protocol does not improve preservation of residual kidney function in incident hemodialysis patients in a randomized controlled trial.

Avoiding excessive dialysis-associated volume depletion may help preserve residual kidney function (RKF). To establish whether knowledge of the estimated normally hydrated weight from bioimpedance measurements (BI-NHW) when setting the post-hemodialysis target weight (TW) might mitigate rate of loss of RKF, we undertook an open label, randomized controlled trial in incident patients receiving HD, with clinicians and patients blinded to bioimpedance readings in controls. A total of 439 patients with over 500 ml urine/day or residual GFR exceeding 3 ml/min/1.73m2 were recruited from 34 United Kingdom centers and randomized 1:1, stratified by center. Fluid assessments were made for up to 24 months using a standardized proforma in both groups, supplemented by availability of BI-NHW in the intervention group. Primary outcome was time to anuria, analyzed using competing-risk survival models adjusted for baseline characteristics, by intention to treat. Secondary outcomes included rate of RKF decline (mean urea and creatinine clearance), blood pressure and patient-reported outcomes. There were no group differences in cause-specific hazard rates of anuria (0.751; 95% confidence interval (0.459, 1.229)) or sub-distribution hazard rates (0.742 (0.453, 1.215)). RKF decline was markedly slower than anticipated, pooled linear rates in year 1: -0.178 (-0.196, -0.159)), year 2: -0.061 (-0.086, -0.036)) ml/min/1.73m2/month. Blood pressure and patient-reported outcomes did not differ by group. The mean difference agreement between TW and BI-NHW was similar for both groups, Bioimpedance: -0.04 kg; Control: -0.25 kg. Thus, use of a standardized clinical protocol for fluid assessment when setting TW is associated with excellent preservation of RKF. Hence, bioimpedance measurements are not necessary to achieve this.

Systematic review and meta-analysis of preoperative interventions to support the maturation of arteriovenous fistulae in patients with advanced kidney disease.

BACKGROUND: There is great potential to improve outcomes of arteriovenous fistulas (AVFs) by focusing more on the preoperative period of AVF creation. We aim to systematically review the evidence on safety and efficacy of various preoperative interventions that have been tried to improve AVF maturation and success rate. METHODS: We searched five databases: PubMed, Embase, CINAHL, Cochrane Library and King's Fund Library. Experimental studies that investigated the effect of various preoperative interventions to improve AVF outcomes among advanced chronic kidney disease (CKD) patients were searched. The effect size for primary outcome was calculated as the weighted mean difference in the final vessel calibre, rate of AVF maturation or primary failure between the intervention and control arm. We also assessed adverse effects and dropout rates. This review was preregistered in the International Prospective Register of Systematic Reviews (CRD42020193257). RESULTS: Eight eligible studies were identified involving three types of intervention: hand exercise (n = 6), cholecalciferol supplementation (n = 1) and pneumatic compression of the arm using a Fist Assist device (n = 1). The overall effect size of hand exercise on distal cephalic vein calibre was 0.24 mm [95% confidence interval (CI) 0.03-0.45] on meta-analysis of hand exercise studies. On restricting analysis to two randomized controlled trials (RCTs) that had independent control groups, the effect size was higher, at 0.29 mm (95% CI 0.11-0.47). Hand exercise was a well-tolerated intervention, especially when confined to the first 4 weeks. DISCUSSION: Hand exercise is the predominant intervention tried in the preoperative period of AVF creation, although there is methodological heterogeneity. Intermittent pneumatic compression using a Fist Assist device is a novel intervention that has shown some promise. Well-designed prospective RCTs are needed on preoperative interventions among advanced CKD patients, aimed at improving AVF outcomes.

Impact of the COVID-19 pandemic on services for patients with chronic kidney disease: findings of a national survey of UK kidney centres.

BACKGROUND: Services for patients with kidney disease underwent radical adaptations in response to the COVID-19 pandemic. We undertook an online national survey of UK kidney centres to understand the nature, range, and degree of variation in these changes and to explore factors contributing to differing practice. METHODS: The survey was designed by a multidisciplinary team of kidney professionals, service users and researchers. It enquired about centre services and staffing, including psychosocial provision, and changes to these in response to the COVID-19 pandemic. Links to the survey were sent to all 68 UK kidney centres and remained active from December 2021 to April 2022, and a revised version to nurses in late 2022 for additional data. Quantitative data were analysed descriptively. Content analysis on free-text responses identified common themes. RESULTS: Analysable responses were received from 41 out of the 68 UK centres (60%), with partial data from an additional 7 (11%). Adaptations were system-wide and affected all aspects of service provision. Some changes were almost universal such as virtual consultations for outpatient appointments, with significant variation in others. Outpatient activity varied from fully maintained to suspended. Many centres reduced peritoneal dialysis access provision but in some this was increased. Centres considered that changes to transplant surgical services and for patients with advanced CKD approaching end-stage kidney disease had the greatest impact on patients. Few centres implemented adjustments aimed at vulnerable and underrepresented groups, including the frail elderly, people with language and communication needs, and those with mental health needs. Communication issues were attributed to rapid evolution of the pandemic, changing planning guidance and lack of resources. Staffing shortages, involving all staff groups particularly nurses, mainly due to COVID-19 infection and redeployment, were compounded by deficiencies in staffing establishments and high vacancy levels. Centres cited three main lessons influencing future service delivery, the need for service redesign, improvements in communication, and better support for staff. CONCLUSION: Kidney centre responses to the pandemic involved adaptations across the whole service. Though some changes were almost universal, there was wide variation in other areas. Exploring the role of centre characteristics may help planning for potential future severe service disruptions.

A multicenter feasibility randomized controlled trial to assess the impact of incremental versus conventional initiation of hemodialysis on residual kidney function.

Twice-weekly hemodialysis, as part of incremental initiation, has reported benefits including preservation of residual kidney function (RKF). To explore this, we initiated a randomized controlled feasibility trial examining 55 incident hemodialysis patients with urea clearance of 3 ml/min/1.73 m2 or more across four centers in the United Kingdom randomized to standard or incremental schedules for 12 months. Incremental hemodialysis involved twice-weekly sessions, upwardly adjusting hemodialysis dose as RKF was lost, maintaining total (Dialysis+Renal) Std Kt/V above 2. Standard hemodialysis was thrice weekly for 3.5-4 hours, minimum Dialysis Std Kt/V of 2. Primary outcomes were feasibility parameters and effect size of group differences in rate of loss of RKF at six months. Health care cost impact and patient-reported outcomes were explored. Around one-third of patients met eligibility criteria. Half agreed to randomization; 26 received standard hemodialysis and 29 incremental. At 12 months, 21 incremental patients remained in the study vs 12 in the standard arm with no group differences in the urea clearance slope. Ninety-two percent of incremental and 75% of standard arm patients had a urea clearance of 2 ml/min/1.73 m2 or more at six months. Serious adverse events were less frequent in incremental patients (Incidence Rate Ratio 0.47, confidence interval 0.27-0.81). Serum bicarbonate was significantly lower in incremental patients indicating supplementation may be required. There were three deaths in each arm. Blood pressure, extracellular fluid and patient-reported outcomes were similar. There was no signal of benefit of incremental hemodialysis in terms of protection of RKF or Quality of Life score. Median incremental hemodialysis costs were significantly lower compared to standard hemodialysis. Thus, incremental hemodialysis appears safe and cost-saving in incident patients with adequate RKF, justifying a definitive trial.

Energy expenditure estimates in chronic kidney disease using a novel physical activity questionnaire.

BACKGROUND: Physical activity (PA) levels are low in patients with advanced chronic kidney disease (CKD), and associate with increased morbidity and mortality. Reliable tools to assess PA in CKD are scarce. We aimed to develop and validate a novel PA questionnaire for use in CKD (CKD-PAQ). METHODS: In Phase 1, a prototype questionnaire was developed based on the validated recent PAQ (RPAQ). Structured feedback on item relevance and clarity was obtained from 40 CKD patients. In Phase 2, the questionnaire was refined in three iterations in a total of 226 CKD patients against 7-day accelerometer and RPAQ measurements. In Phase 3, the definitive CKD-PAQ was compared with RPAQ in 523 CKD patients. RESULTS: In the final iteration of Phase 2, CKD-PAQ data were compared with accelerometer-derived and RPAQ data in 60 patients. Mean daily metabolic equivalent of task (MET) and total energy expenditure (TEE) levels were similar by all methods. Intraclass correlation coefficients showed fair (MET) and good (TEE) agreement between accelerometry and both CKD-PAQ and RPAQ. Agreement between questionnaires was excellent. The mean [standard deviation (SD)] daily MET bias was 0.035 (0.312) for CKD-PAQ and 0.018 (0.326) for RPAQ. The mean (SD) TEE bias was 91 (518) for CKD-PAQ and 44 (548) kcal for RPAQ. Limits of agreement (LOA) were wide for both parameters, with less dispersion of CKD-PAQ values. In Phase 3, agreement between questionnaires was good (MET) and excellent (TEE). Bias of CKD-PAQ-derived mean (SD) daily MET from RPAQ-derived values was 0.031 (0.193), with 95% LOA -0.346 to 0.409. Corresponding mean (SD) values for TEE were 48 (325) and -588 to 685 kcal/day. CKD-PAQ appeared to improve discrimination between low activity groups. CONCLUSIONS: CKD-PAQ performs comparably to the RPAQ though it is shorter, easier to complete, and may better capture low-level activity and improve discrimination between low activity groups.

Measuring patients' experience with renal services in the UK: development and validation of the Kidney PREM.

BACKGROUND: Patient experience is a recognized aspect of quality of care for people with chronic kidney disease (CKD), but current patient-reported experience measures (PREMs) only focus on dialysis care. We developed and validated the Kidney PREM to assess patients' experience with renal services in secondary care for any CKD stage or treatment (transplant, haemodialysis and peritoneal dialysis). METHODS: We developed the Kidney PREM in two phases, informed by a multidisciplinary expert group to ensure face validity. We organized three national data collections (2016-8) to investigate item response profiles and to conduct exploratory and confirmatory analyses to assess internal consistency. We also explored content validity in cognitive interviews and evaluated test-retest reliability. Finally, we developed the Kidney PREM Short Form for more frequent measurement of patient experience to inform local service improvements. RESULTS: We analysed 32 959 responses across data collections, with the 2018 collection covering all 71 UK renal centres. The Kidney PREM final version consisted of 38 items grouped into 13 themes, all pertaining to one underlying dimension reflecting the construct of 'patient experience' with high internal consistency (Cronbach's α = 0.94). The Kidney PREM Short Form consisted of 15 items across the same 13 themes. CONCLUSIONS: The Kidney PREM supports the collection of reliable information on patient experience that people with CKD consider relevant, regardless of CKD stage or treatment modality. Kidney PREM data have the potential to guide local and national initiatives to improve patients' experiences with renal services in the UK and other countries.

2-Oxothiazolidine-4-carboxylic acid inhibits vascular calcification via induction of glutathione synthesis.

Arterial medial calcification (AMC), the deposition of hydroxyapatite in the medial layer of the arteries, is a known risk factor for cardiovascular events. Oxidative stress is a known inducer of AMC and endogenous antioxidants, such as glutathione (GSH), may prevent calcification. GSH synthesis, however, can be limited by cysteine levels. Therefore, we assessed the effects of the cysteine prodrug 2-oxothiazolidine-4-carboxylic acid (OTC), on vascular smooth muscle cell (VSMC) calcification to ascertain its therapeutic potential. Human aortic VSMCs were cultured in basal or mineralising medium (1 mM calcium chloride/sodium phosphate) and treated with OTC (1-5 mM) for 7 days. Cell-based assays and western blot analysis were performed to assess cell differentiation and function. OTC inhibited calcification ≤90%, which was associated with increased ectonucleotide pyrophosphatase/phosphodiesterase activity, and reduced apoptosis. In calcifying cells, OTC downregulated protein expression of osteoblast markers (Runt-related transcription factor 2 and osteopontin), while maintaining expression of VSMC markers (smooth muscle protein 22α and α-smooth muscle actin). GSH levels were significantly reduced by 90% in VSMCs cultured in calcifying conditions, which was associated with declines in expression of gamma-glutamylcysteine synthetase and GSH synthetase. Treatment of calcifying cells with OTC blocked the reduction in expression of both enzymes and prevented the decline in GSH. This study shows OTC to be a potent and effective inhibitor of in vitro VSMC calcification. It appears to maintain GSH synthesis which may, in turn, prevent apoptosis and VSMCs gaining osteoblast-like characteristics. These findings may be of clinical relevance and raise the possibility that treatment with OTC could benefit patients susceptible to AMC.

Using a generic definition of cachexia in patients with kidney disease receiving haemodialysis: a longitudinal (pilot) study.

BACKGROUND: Research indicates that cachexia is common among persons with chronic illnesses and is associated with increased morbidity and mortality. However, there continues to be an absence of a uniformed disease-specific definition for cachexia in chronic kidney disease (CKD) patient populations. OBJECTIVE: The primary objective was to identify cachexia in patients receiving haemodialysis (HD) using a generic definition and then follow up on these patients for 12 months. METHOD: This was a longitudinal study of adult chronic HD patients attending two hospital HD units in the UK. Multiple measures relevant to cachexia, including body mass index (BMI), muscle mass [mid-upper arm muscle circumference (MUAMC)], handgrip strength (HGS), fatigue [Functional Assessment of Chronic Illness Therapy (FACIT)], appetite [Functional Assessment of Anorexia/Cachexia Therapy (FAACT)] and biomarkers [C-reactive protein (CRP), serum albumin, haemoglobin and erythropoietin resistance index (ERI)] were recorded. Baseline analysis included group differences analysed using an independent t-test, dichotomized values using the χ2 test and prevalence were reported using the Statistical Package for the Social Sciences 24 (IBM, Armonk, NY, USA). Longitudinal analysis was conducted using repeated measures analysis. RESULTS: A total of 106 patients (30 females and 76 males) were recruited with a mean age of 67.6 years [standard deviation (SD) 13.18] and dialysis vintage of 4.92 years (SD 6.12). At baseline, 17 patients were identified as cachectic, having had reported weight loss (e.g. >5% for >6 months) or BMI <20 kg/m2 and three or more clinical characteristics of cachexia. Seventy patients were available for analysis at 12 months (11 cachectic versus 59 not cachectic). FAACT and urea reduction ratio statistically distinguished cachectic patients (P = 0.001). However, measures of weight, BMI, MUAMC, HGS, CRP, ERI and FACIT tended to worsen in cachectic patients. CONCLUSION: Globally, cachexia is a severe but frequently underrecognized problem. This is the first study to apply the defined characteristics of cachexia to a representative sample of patients receiving HD. Further, more extensive studies are required to establish a phenotype of cachexia in advanced CKD.

Effect of Chronic Kidney Disease on Metabolic Rate: Studies Using Doubly Labelled Water.

OBJECTIVE: The causes of protein malnutrition and body composition changes in chronic kidney disease (CKD) are poorly understood. Alterations to metabolic rate caused by CKD may be a contributor. Using the doubly labeled water technique and indirect calorimetry, we set out to determine whether reduced glomerular filtration rate is associated with alterations to total energy expenditure (TEE) and resting energy expenditure (REE). We also aimed to determine whether TEE in patients with CKD can be easily predicted from a physical activity questionnaire. METHODS: In a prospective, observational study we evaluated 80 patients (52 men; mean age 56.7 ± 16.2 years) with CKD ranging from stage 1 to stage 5 with estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). TEE was measured using doubly labeled water isotope excretion over 14 days (TEEDLW), REE by indirect calorimetry (REEIndirectCal) and physical activity level using the Stanford 7-day recall questionnaire. RESULTS: eGFR did not correlate with TEEDLW and REEIndirectCal. Findings with weight-adjusted energy measures were similar. REEIndirectCal and TEEDLW were significantly lower in patients whose eGFR was <50 mL/min/1.73 m2 and those with higher levels. There were similar findings with respect to weight-adjusted energy measures. In multivariable analysis, age, sex, and weight were independent predictors of TEEDLW and REEIndirectCal. eGFR did not predict TEE or REE in either of these models. CONCLUSION: There was no direct relationship between reduced renal function and metabolic rate. Differences in energy metabolism at lower levels of glomerular filtration rate are more likely to be due to factors such as age, body composition, and physical activity.