Impact of very low dose rivaroxaban in addition to dual antiplatelet therapy on endogenous fibrinolysis in acute coronary syndrome: The VaLiDate-R study.

BACKGROUND: Impaired endogenous fibrinolysis is adverse cardiovascular risk factor in acute coronary syndrome (ACS) patients. Addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy (DAPT) reduces cardiovascular events but increases bleeding. OBJECTIVE: We aimed to assess whether addition of VLDR to DAPT can enhance endogenous fibrinolysis. METHODS: In a prospective, open-label trial, we assessed endogenous fibrinolysis in whole blood, in 549 patients with ACS using the Global Thrombosis Test (GTT) and Thromboelastography (TEG). Patients (n = 180) who demonstrated impaired endogenous fibrinolysis (lysis time [LT] >2000s with the GTT) were randomised 1:1:1 to (i) clopidogrel 75 mg daily; (ii) clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily; or (iii) ticagrelor 90 mg twice daily, for 30 days, in addition to aspirin. Fibrinolytic status was assessed at 0, 2, 4 and 8 weeks. The primary outcome was the change in LT from admission to week 4. We also measured thrombotic occlusion time (OT) at high shear, and rivaroxaban level. RESULTS: There was no difference between the groups with respect to LT or clot lysis with TEG, and no change in these parameters compared to baseline during study drug allocation. In the rivaroxaban plus clopidogrel group, OT was prolonged compared to the other groups, although rivaroxaban levels were low, suggesting non-compliance. CONCLUSION: Addition of rivaroxaban 2.5 mg twice daily to DAPT does not affect endogenous fibrinolysis of thrombus formed at either high or low shear. Further studies are needed to determine whether higher doses of rivaroxaban can favourably modulate fibrinolysis. CONDENSED ABSTRACT: Impaired endogenous fibrinolysis is a strong risk factor in ACS. We aimed to assess whether adding very low dose rivaroxaban (VLDR) to DAPT can enhance fibrinolysis. Fibrin and clot lysis were assessed in whole blood. ACS patients with impaired fibrinolysis were randomised 1:1:1 to clopidogrel 75 mg daily; clopidogrel 75 mg plus VLDR; or ticagrelor 90 mg twice daily, in addition to aspirin. At 30-days, there was no difference in lysis time between the groups, nor change from baseline. VLDR does not improve fibrinolysis at high or low shear. Further studies are needed to determine whether alternative antithrombotic regimens can enhance endogenous fibrinolysis.

Measures of treatment burden in dialysis: A scoping review.

BACKGROUND: Dialysis is a life-sustaining treatment for patients with advanced kidney failure, but it is extremely burdensome. Despite this, there are very few tools available to assess treatment burden within the dialysis population. OBJECTIVE: To conduct a scoping review of generic and disease-specific measures of treatment burden in chronic kidney disease, and assess their suitability for use within the dialysis population. DESIGN: We searched CINAHL, MEDLINE and the Cochrane Library for kidney disease-specific measures of treatment burden. Studies were initially included if they described the development, validation or use of a treatment burden measure or associated concept (e.g., measures of treatment satisfaction, quality of life, illness intrusiveness, disease burden etc.) in adult patients with chronic kidney disease. We also updated a previous scoping review exploring measures of treatment burden in chronic disease to identify generic treatment burden measures. RESULTS: One-hundred and two measures of treatment burden or associated concepts were identified. Four direct measures and two indirect measures of treatment burden were assessed, using adapted established criteria, for suitability for use within the dialysis population. The researchers outlined eight key dimensions of treatment burden: medication, financial, administrative, lifestyle, health care, time/travel, dialysis-specific factors, and health inequality. None of the measures adequately assessed all dimensions of treatment burden. CONCLUSION: Current measures of treatment burden in dialysis are inadequate to capture the spectrum of issues that matter to patients. There is a need for dialysis-specific burdens and health inequality to be assessed when exploring treatment burden to advance patient care.

Impact of incremental initiation of haemodialysis on mortality: a systematic review and meta-analysis.

BACKGROUND: Incremental haemodialysis initiation entails lower sessional duration and/or frequency than the standard 4 h thrice-weekly approach. Dialysis dose is increased as residual kidney function (RKF) declines. This systematic review evaluates its safety, efficacy and cost-effectiveness. METHODS: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library databases from inception to 27 February 2022. Eligible studies compared incremental haemodialysis (sessions either fewer than three times weekly or of duration <3.5 h) with standard treatment. The primary outcome was mortality. Secondary outcomes included treatment-emergent adverse events, loss of RKF, quality of life and cost effectiveness. The study protocol was prospectively registered. Risk of bias assessment used the Newcastle-Ottawa Scale and the revised Cochrane risk of bias tool, as appropriate. Meta-analyses were undertaken in Review Manager, Version 5.4. RESULTS: A total of 644 records were identified. Twenty-six met the inclusion criteria, including 22 cohort studies and two randomized controlled trials (RCTs). Sample size ranged from 48 to 50 596 participants (total 101 476). We found no mortality differences (hazard ratio = 0.99; 95% CI 0.80-1.24). Cohort studies suggested similar hospitalization rates though the two small RCTs suggested less hospitalization after incremental initiation (relative risk = 0.31; 95% CI 0.18-0.54). Data on other treatment-emergent adverse events and quality of life was limited. Observational studies suggested reduced loss of RKF in incremental haemodialysis. This was not supported by RCT data. Four studies reported reduced costs of incremental treatments. CONCLUSIONS: Incremental initiation of haemodialysis does not confer greater risk of mortality compared with standard treatment. Hospitalization may be reduced and costs are lower.

Prevalence and outcomes of chronic liver disease in patients receiving dialysis: systematic review and meta-analysis.

Background: Patients receiving dialysis for end-stage kidney disease (ESKD) commonly co-exhibit risk factors for hepatic impairment. This systematic review and meta-analysis aimed to quantify the coexistence of chronic liver disease (CLD) and characterize risk factors and outcomes. Methods: We searched the following databases from inception to May 2021: CINAHL, Cochrane Library, Embase, Kings Fund Library, MEDLINE and PubMed. The protocol was pre-registered on PROSPERO (study ID: CRD42020206486). Studies were assessed against three inclusion criteria: adults (>18 years) with ESKD receiving dialysis, primary outcome involving CLD prevalence and publications in English. Moderator analysis was performed for age, gender, study size and publication year. Sensitivity analysis was performed where applicable by removing outlier results and studies at high risk of bias. Results: Searches yielded 7195 articles; of these 15 met the inclusion criteria. A total of 320 777 patients were included. The prevalence of cirrhosis and non-alcoholic fatty liver disease (NAFLD) was 5% and 55%, respectively. Individuals with CLD had 2-fold higher mortality than those without {odds ratio [OR] 2.19 [95% confidence interval (CI) 1.39-3.45]}. Hepatitis B [OR 13.47 (95% CI 1.37-132.55)] and hepatitis C [OR 7.05 (95% CI 4.00-12.45)], but not diabetes, conferred increased cirrhosis risk. All studies examining NAFLD were judged to be at high risk of bias. We found no data on non-alcoholic steatohepatitis (NASH). Deaths from CLD, cancer and infection were greater among cirrhotic patients. Conclusions: CLD is prevalent in dialysis patients. Hepatitis B and C confer increased risk of CLD. The impact of NAFLD and NASH cirrhosis requires further study. CLD is associated with an increased risk of mortality in this setting.

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.

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.

Patient Preferences for Longer or More Frequent In-Center Hemodialysis Regimens: A Multicenter Discrete Choice Study.

RATIONALE & OBJECTIVE: Longer and more frequent hemodialysis sessions are associated with both benefits and harms. However, their relative importance to patients and how they influence acceptability for patients have not been quantified. STUDY DESIGN: Discrete-choice experiment in which a scenario followed by 12 treatment choice sets were presented to patients in conjunction with varying information about the clinical impact of the treatments offered. SETTING & PARTICIPANTS: Patients with kidney failure treated with maintenance dialysis for≥1 year in 5 UK kidney centers. PREDICTORS: Length and frequency of hemodialysis sessions and their prior reported associations with survival, quality of life, need for fluid restriction, hospitalization, and vascular access complications. OUTCOME: Selection of longer (4.5 hours) or more frequent (4 sessions per week) hemodialysis regimens versus remaining on 3 sessions per week with session lengths of 4 hours. ANALYTICAL APPROACH: Multinomial mixed effects logistic regression estimating the relative influence of different levels of the predictors on the selection of longer and more frequent dialysis, controlling for patient demographic characteristics. RESULTS: Among 183 prevalent in-center hemodialysis patients (mean age of 63.7 years, mean dialysis vintage of 4.7 years), 38.3% (70 of 183) always chose to remain on regimens of 3 sessions per week with session duration of 4 hours. Depicted associations of increasing survival and quality of life, reduced need for fluid restriction, and avoiding additional access complications were all significantly associated with choosing longer or more frequent treatment regimens. Younger age, fatigue, previous experience of vascular access complications, absence of heart failure, and shorter travel time to dialysis centers were associated with preference for 4 sessions per week. Patients expressed willingness to trade up to 2 years of life to avoid regimens of 4 sessions per week or access complications. After applying estimated treatment benefits and harms from existing literature, the fully adjusted model revealed that 27.1% would choose longer regimens delivered 3 times per week and 34.3% would choose 4 hours 4 times per week. Analogous estimates for younger fatigued patients living near their unit were 23.5% and 62.5%, respectively. LIMITATIONS: Estimates were based on stated preferences rather than observed behaviors. Predicted acceptance of regimens was derived from data on treatment benefits and harms largely sourced from observational studies. CONCLUSIONS: Predicted acceptance of longer and more frequent hemodialysis regimens substantially exceeds their use in current clinical practice. These findings underscore the need for robust data on clinical effectiveness of these more intensive regimens and more extensive consideration of patient choice in the selection of dialysis regimens.

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.

Impact of incremental versus conventional initiation of haemodialysis on residual kidney function: study protocol for a multicentre feasibility randomised controlled trial.

INTRODUCTION: Preserving residual kidney function (RKF) may be beneficial to patients on haemodialysis (HD) and it has been proposed that commencing dialysis incrementally rather than three times a week may preserve RKF. In Incremental HD, target dose includes a contribution from RKF, which is added to HD dose, allowing individualisation of the HD prescription. We will conduct a feasibility randomised controlled trial (RCT) comparing incremental HD and conventional three times weekly treatments in incident HD patients. The study is designed also to provide pilot data to allow determination of effect size to power a definitive study. METHODS AND ANALYSIS: After screening to ensure native renal urea clearance >3 mL/min/1.73 m2, the study will randomise 54 patients within 3 months of HD initiation to conventional in-centre thrice weekly dialysis or incremental in-centre HD commencing 2 days a week. Subjects will be followed up for 12 months. The study will be carried out across four UK renal centres.The primary outcome is to evaluate the feasibility of conducting a definitive RCT and to estimate the difference in rate of decline of RKF between the two groups at 6 and 12 months time points. Secondary outcomes will include the impact of dialysis intensity on vascular access events, major adverse cardiac events and survival. Impact of dialysis intensity on patient-reported outcomes measures, cognition and frailty will be assessed using EQ-5D-5L, PHQ-9, Illness Intrusiveness Rating Score, Montreal Cognitive assessment and Clinical Frailty Score. Safety outcomes include hospitalisation, fluid overload episodes, hyperkalaemia events and vascular access events.This study will inform the design of a definitive study, adequately powered to determine whether RKF is better preserved after incremental HD initiation compared with conventional initiation. ETHICS AND DISSEMINATION: Ethics approval has been granted by Cambridge South Research Ethics Committee, United Kingdom(REC17/EE/0311). Results will be disseminated via peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03418181.

Beta-glucans in advanced CKD: role in endotoxaemia and inflammation.

BACKGROUND/AIMS: (1-3)-ß-D glucans (BG) are cellular components of yeasts and fungi. Elevated blood levels may be an adjunct in diagnosing invasive fungal infection, though can be high in dialysis patients without fungaemia. BG can also induce false positive signals in endotoxin detection assays (Limulus Amoebocyte Lysate [LAL] assay). We explored the relationship between BG levels, renal impairment, endotoxaemia and inflammation. METHODS: We measured serum BG levels, markers of inflammation and blood endotoxin levels in 20 controls, 20 with stages 1-3 chronic kidney disease (CKD), 20 with stages 4-5 CKD, 15 on peritoneal dialysis (PD) and 60 on haemodialysis (HD). Another 30 patients were studied before and after HD initiation. RESULTS: BG levels increased with advancing CKD, being highest in HD patients, 22% of whom had elevated levels (> 80 pg/ml). Levels increased significantly following HD initiation. Levels also correlated positively with CRP, TNFα, IL-6 levels, independently of CKD stage. Blood endotoxin was detectable by LAL assays in 10-53% of the CKD cohort, being most prevalent in the HD group, and correlating positively with BG levels. Adding BG blocking agent to the assay reduced endotoxin detection confining it to only 5% of HD patients. Levels of inflammatory markers were higher in those with detectable endotoxin - whether false- or true positives. CONCLUSION: BG levels increased with decreasing renal function, being highest in dialysis patients. High BG levels were associated with false positive blood endotoxin signals, and with markers of inflammation, independently of CKD stage. The cause for high BG levels is unknown but could reflect increased gut permeability and altered mononuclear phagocytic system function.

Unexplained inflammation in end-stage kidney disease: Is the combination of enhanced gastrointestinal permeability and reticuloendothelial dysfunction its cause?

Unexplained chronic inflammation is prevalent in end-stage kidney disease, and contributes toward accelerated cardiovascular disease, and premature death. The source of inflammation is unclear, although increased gastrointestinal permeability is a likely contributory factor. Whether a "leaky" gut leads to penetration of the systemic circulation by gut-derived pathogens is at least partly dependent on Kupffer cell function. These resident liver macrophages are an important part of the reticuloendothelial system (RES), and there is evidence for Kupffer cell and reticuloendothelial dysfunction in chronic kidney disease. These observations are compatible with the inflammatory milieu of chronic kidney disease being of gut origin. Measuring gut permeability in chronic kidney disease is challenging. Use of fecal biomarkers and other novel serum biomarkers represent potential alternative tools. One such marker is (1-3)-Beta-D-glucan, a polysaccharide constituent of many fungal, bacterial, and plant cell walls; levels of (1-3)-Beta-D-glucan are elevated in hemodialysis patients. Gastrointestinal permeability and impaired removal by the RES may contribute to these high levels, suggesting potential importance as a biomarker. High levels of (1-3)-Beta-D-glucan also falsely elevate endotoxin measurements. Measuring the contribution of gastrointestinal permeability and RES dysfunction to systemic inflammation may be an important step in designing therapies to reduce systemic inflammation in chronic kidney disease.

Acute haemodynamic changes during haemodialysis do not exacerbate gut hyperpermeability.

INTRODUCTION: The gastrointestinal tract is a potential source of inflammation in dialysis patients. In vitro studies suggest breakdown of the gut barrier in uraemia leading to increased intestinal permeability and it is hypothesised that haemodialysis exacerbates this problem due to mesenteric ischaemia induced by blood volume changes during treatment. METHOD: The effect of haemodialysis on intestinal permeability was studied in ten haemodialysis patients and compared with five controls. Intestinal permeability was assessed by measuring the differential absorption of four orally administered sugar probes which provides an index of small and whole bowel permeability. A multi-sugar solution (containing lactulose, rhamnose, sucralose and erythritol) was orally administered after an overnight fast. Plasma levels of all sugar probes were measured hourly for 10 h post-administration. In haemodialysis patients, the procedure was carried out twice - once on a non-dialysis day and once immediately after haemodialysis. RESULTS: Area under curve (AUC) for lactulose:rhamnose (L:R) ratio and sucralose:erythritol (S:E) ratio was similar post-dialysis and on non-dialysis days. AUC for L:R was higher in haemodialysis patients compared with controls (0.071 vs. 0.034, P=0.001), AUC for S:E ratio was not significantly different. Levels of lactulose, sucralose and erythritol were elevated and retained longer in haemodialysis patients compared with controls due to dependence of sugars on kidney function for clearance. CONCLUSION: We found no significant acute changes in intestinal permeability in relation to the haemodialysis procedure. Valid comparison of intestinal permeability between controls and haemodialysis patients was not possible due to the strong influence of kidney function on sugar levels.

Initiating haemodialysis twice-weekly as part of an incremental programme may protect residual kidney function.

BACKGROUND: Initiating twice-weekly haemodialysis (2×HD) in patients who retain significant residual kidney function (RKF) may have benefits. We aimed to determine differences between patients initiated on twice- and thrice-weekly regimes, with respect to loss of kidney function, survival and other safety parameters. METHODS: We conducted a single-centre retrospective study of patients initiating dialysis with a residual urea clearance (KRU) of ≥3 mL/min, over a 20-year period. Patients who had 2×HD for ≥3 months during the 12 months following initiation of 2×HD were identified for comparison with those dialysed thrice-weekly (3×HD). RESULTS: The 2×HD group consisted of 154 patients, and the 3×HD group 411 patients. The 2×HD patients were younger (59 ± 15 versus 62 ± 15 years: P = 0.014) and weighed less (70 ± 16 versus 80 ± 18 kg: P < 0.001). More were females (34% versus 27%: P = 0.004). Fewer had diabetes (25% versus 34%: P = 0.04) and peripheral vascular disease (PVD) (13% versus 23%: P = 0.008). Baseline KRU was similar in both groups (5.3 ± 2.4 for 2 × HD versus 5.1 ± 2.8 mL/min for 3 × HD: P = 0.507). In a mixed effects model correcting for between-group differences in comorbidities and demographics, 3×HD was associated with increased rate of loss of KRU and separation of KRU. In separate mixed effects models, group (2×HD versus 3×HD) was not associated with differences in serum potassium or phosphate, and the groups did not differ with respect to total standard Kt/V. Survival, adjusted for age, gender, weight, baseline KRU and comorbidity (prevalence of diabetes, cardiac disease, PVD and malignancy) was greater in the 2×HD group (hazard ratio 0.755: P = 0.044). In sub-analyses, the survival benefit was confined to women, and those of less than median bodyweight. CONCLUSION: 2×HD initiation as part of an incremental programme with regular monthly monitoring of KRU was safe and associated with a reduced rate of loss of RKF early after dialysis initiation and improved survival. Randomized controlled trials of this approach are indicated.

Indexing dialysis dose for gender, body size and physical activity: Impact on survival.

Current practice basing dialysis dose on urea distribution volume (V) has been questioned. We explored the impact on survival of scaling dialysis dose (Kt) to parameters reflective of metabolic activity. In a multicentre prospective cohort study of 1500 patients on thrice-weekly haemodialysis, body surface area (BSA) and resting energy expenditure (REE) were estimated using validated equations and physical activity by the Recent Physical Activity Questionnaire. Total energy expenditure (TEE) was estimated from REE and physical activity data. Kt was calculated from delivered (single-pool Kt/V)*Watson V. Kt/BSA, Kt/REE and Kt/TEE were then calculated at baseline and 6 monthly during follow-up for 2 years. In adjusted Cox models Kt/TEE, Kt/BSA, Kt/REE, in that order, had lower hazard ratios for death than single-pool Kt/V. On the basis of adjusted survival differences, putative minimum target doses were estimated for Kt/BSA as 27119 ml/m2 and Kt/TEE as 25.79 ml/kcal. We identified spKt/V values equivalent to these estimated targets, ranging from 1.4 to 1.8 in patient groups based on gender, body size and physical activity. For sedentary patients, the minimum target dose was 1.4 for large males, 1.5 for small males and 1.7 for women. For active patients the target was 1.8 irrespective of gender and body-weight. Patients achieving these individualised minimum targets had greater adjusted two-year survival compared to those achieving conventional minimum targets. Metabolic activity related parameters, such as Kt/TEE and Kt/BSA, may have a clinically important role in scaling haemodialysis dose. Using such parameters or their spKt/V equivalents to adjust minimum target doses based on gender, body size and habitual physical activity may have a positive impact on survival.

The Effect of Intra-Dialytic Exercise on Inflammation and Blood Endotoxin Levels.

BACKGROUND: In healthy individuals, an acute inflammatory response occurs after intense exercise due to gut ischaemia and intestinal bacterial endotoxin translocation into the bloodstream. This process maybe exacerbated in patients who exercise during dialysis due to large volume shifts experienced by many during haemodialysis (HD). The acute effect of intra-dialytic exercise on blood endotoxins and inflammation is not known. METHOD: The effect of intra-dialytic exercise on blood endotoxin and inflammation was investigated in 10 patients and compared with resting haemodialysis. Blood was measured for endotoxin and inflammatory biomarkers before and after dialysis. RESULT: With the exception of one sample, all samples tested negative for endotoxin. Intra-dialytic exercise attenuated the rise of interleukin-6, tumour necrosis factor-α and high-sensitivity C-reactive protein after the HD procedure. CONCLUSION: Intra-dialytic exercise was not associated with an observable rise in blood endotoxin, although it may ameliorate the inflammatory effects of the HD procedure. Larger studies are needed to confirm this finding.

Scaling Hemodialysis Target Dose to Reflect Body Surface Area, Metabolic Activity, and Protein Catabolic Rate: A Prospective, Cross-sectional Study.

BACKGROUND: Women and small men treated by hemodialysis (HD) have reduced survival. This may be due to use of total-body water (V) as the normalizing factor for dialysis dosing. In this study, we explored the equivalent dialysis dose that would be delivered using alternative scaling parameters matching the current recommended minimum Kt/V target of 1.2. STUDY DESIGN: Prospective cross-sectional study. SETTING & PARTICIPANTS: 1,500 HD patients on a thrice-weekly schedule, recruited across 5 different centers. PREDICTORS: Age, sex, weight, race/ethnicity, comorbid condition level, and employment status. OUTCOMES: Kt was estimated by multiplying V by 1.2. Kt/body surface area (BSA), Kt/resting energy expenditure (REE), Kt/total energy expenditure (TEE) and Kt/normalized protein catabolic rate (nPCR) equivalent to a target Kt/V of 1.2 were then estimated by dividing Kt by the respective parameters. MEASUREMENTS: Anthropometry, HD adequacy details, and BSA were obtained by standard procedures. REE was estimated using a novel validated equation. TEE was calculated from physical activity data obtained using the Recent Physical Activity Questionnaire. nPCR was estimated using a standard formula. RESULTS: Mean BSA was 1.87m2; mean REE, 1,545kcal/d; mean TEE, 1,841kcal/d; and mean nPCR, 1.03g/kg/d. For Kt/V of 1.2, there was a wide range of equivalent doses expressed as Kt/BSA, Kt/REE, Kt/TEE, and Kt/nPCR. The mean equivalent dose was lower in women for all 4 parameters (P<0.001). Small men would also receive lower doses compared with larger men. Younger patients, those with low comorbidity, those employed, and those of South Asian race/ethnicity would receive significantly lower dialysis doses with current practice. LIMITATIONS: Cross-sectional study; physical activity data collected by an activity questionnaire. CONCLUSIONS: Current dosing practices may risk underdialysis in women, men of smaller body size, and specific subgroups of patients. Using BSA-, REE-, or TEE-based dialysis prescription would result in higher dose delivery in these patients.

Measuring Residual Renal Function in Hemodialysis Patients without Urine Collection.

Many patients on hemodialysis retain significant residual renal function (RRF) but currently measurement of RRF in routine clinical practice can only be achieved using inter-dialytic urine collections to measure urea and creatinine clearances. Urine collections are difficult and inconvenient for patients and staff, and therefore RRF is not universally measured. Methods to assess RRF without reliance on urine collections are needed since RRF provides useful clinical and prognostic information and also permits the application of incremental hemodialysis techniques. Significant efforts have been made to explore the use of serum based biomarkers such as cystatin C, ß-trace protein and ß2 -microglobulin to estimate RRF. This article reviews blood-based biomarkers and novel methods using exogenous filtration markers which show potential in estimating RRF in hemodialysis patients without the need for urine collection.

Attitudes in Patients with Autosomal Dominant Polycystic Kidney Disease Toward Prenatal Diagnosis and Preimplantation Genetic Diagnosis.

AIMS: No recommendations currently exist regarding implementation of both prenatal diagnosis and preimplantation genetic diagnosis (PGD) for autosomal dominant polycystic kidney disease (ADPKD). This study evaluated attitudes in ADPKD patients with either chronic kidney disease (CKD) stages I-IV or end-stage renal failure (ESRF) toward prenatal diagnosis and PGD. METHODS: Ninety-six ADPKD patients were recruited from an outpatient clinic, wards, and dialysis units. Thirty-eight patients had ESRF and 58 had CKD stages I-IV. Participants were given an information sheet on prenatal diagnosis and PGD and subsequently completed a questionnaire. RESULTS: The median age of participants was 51.5 years. Seventeen percent of ADPKD patients with CKD and 18% of ADPKD patients with ESRF would consider prenatal diagnosis and termination of pregnancy for ADPKD. Fifty percent with CKD would have opted for PGD (or might consider it in the future) were it available and funded by the UK National Health Service, compared to 63% in the ESRF group (p = 0.33). Sixty-nine percent in the CKD group and 68% in the ESRF group believed that PGD should be offered to other patients. DISCUSSION: There was a spectrum of attitudes among this cohort. A proportion of patients believe that PGD should be made available to prospective parents with this disease. The discrepancy between the low proportion (17% CKD, 18% ESRF) who would consider prenatal diagnosis and termination of pregnancy and the higher number who hypothetically express an intention or wish to access PGD (50% CKD and 63% ESRF) indicates far greater acceptability for diagnostic methods that occur before embryo implantation. It is not known how the development of methods to identify patients whose renal function is likely to decline rapidly and treatments altering the natural history of ADPKD will affect these attitudes.

Is Endotoxemia in Stable Hemodialysis Patients an Artefact? Limitations of the Limulus Amebocyte Lysate Assay and Role of (1→3)-ß-D Glucan.

BACKGROUND: Elevated blood endotoxin levels are frequently reported in the dialysis population and are strongly linked with inflammation, a major predictor of mortality. Virtually all studies have employed the Limulus Amoebocyte Lysate (LAL) assay to detect endotoxin. However this assay is not endotoxin-specific and can be activated by (1→3)-ß-glucan (BG), a component of fungal cell walls leading to false positive signals. Very few studies have taken account of this. We examined the influence of BG-based activation of the LAL assay on the detection of endotoxemia in this setting. METHOD: We measured plasma endotoxin levels in 50 hemodialysis patients with and without the use of BG-blocking buffers. These buffers inhibit BG activation of the LAL assay to ensure that any signal detected is endotoxin-specific. Blood samples were measured for BG, interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α) to examine the association between endotoxin signals, BG and inflammation. RESULTS: Endotoxin signals were detected in 50% of patients. On repeat measurement with a BG-blocking buffer, all detected endotoxin signals were extinguished. No patient had detectable endotoxemia. Plasma BG levels were significantly elevated in 58% of patients and were higher in those with detectable endotoxin signals using the LAL assay without BG-blocking buffers (78vs.54pg/mL;p<0.001). Endotoxin signal and BG levels did not correlate with levels of TNF-α or IL-6. CONCLUSION: Use of the LAL assay for blood endotoxin detection in dialysis patients has its limitations due to high blood BG. Endotoxemia frequently reported in non-infected hemodialysis patients may be artefactual due to BG interference.