Impact of the Preservation of Residual Kidney Function on Hemodialysis Survival: Results from the BISTRO Trial.

BACKGROUND: Preservation of residual kidney function (RKF) in dialysis patients has been associated with improved survival. RKF in the BISTRO trial was relatively well preserved and here we describe its association with survival during the trial and extended follow-up. METHODS: RKF, measured as the average urea and creatinine clearance (GFR) or 24-hour urine volume was assessed at baseline, one, two and three months and three-monthly up to 2 years in incident haemodialysis patients. Time to event survival data or competing events (transplantation, modality change) were obtained for 50 months post enrolment via data linkage with the UK Renal Registry. Cox proportional hazards regression survival models, including those incorporating change in GFR from baseline as a time-varying variable and joint regression models for longitudinal and survival data (longitudinal models for GFR or urine volume) were used to explore the relationship of RKF preservation with survival. Analyses were adjusted for age, sex, comorbidity and ethnicity. RESULTS: 2919 measures of RKF were made in 387 patients from 32 UK dialysis units. Higher age and comorbidity score associated with increased mortality in all models. Baseline GFR reduced the risk of death (Hazard Ratio: 0.918 95%CI: 0.844, 0.999) per ml/min/1.73m2. A greater fall in GFR and urine volume from baseline was associated with a non-significant increased risk of death as visualised on spline plots. In the joint survival models higher GFR (adjusted HR: 0.88 95%CI 0.80, 0.97) or urine volume (adjusted HR: 0.75 95%CI 0.57, 0.95 per L) at any time point associated with better survival. CONCLUSIONS: Lower RKF during the first two years of haemodialysis is associated with an increased death risk for up to 50 months following dialysis initiation. This adds to a growing body of evidence that interventions to preserve RKF should be developed and tested in clinical trials.

Cost-effectiveness of bioimpedance-guided fluid management in patients undergoing haemodialysis: the BISTRO RCT.

Background: The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. Objectives: To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Design: Within-trial economic evaluation (cost-utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Setting: Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Participants: Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. Intervention: The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. Main outcome measures: The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. Results: The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI -£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI -0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. Limitations: The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Conclusions: Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work: Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. Funding details: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142).

'Bioimpedance' is a measure of how difficult it is for an electric current to pass through a biological object. Bioimpedance is used in devices that assess fluid status (over- or under-hydration) because it is very sensitive to the amount of water in tissue. Bioimpedance can be used in addition to clinical judgement when deciding how much water should be removed from someone with kidney failure during a dialysis treatment session. This is the first study to examine whether using this treatment represents a cost-effective use of National Health Service resources. We carried out an economic evaluation within a large randomised controlled trial in patients with kidney disease undergoing haemodialysis. We calculated the additional costs and quality-adjusted life-years (a measure that combines quality and quantity of life) using established methods. Over 2 years, our study showed that taking into account bioimpedance measurements about target weight resulted in slightly lower costs and marginally more quality-adjusted life-years, although there is uncertainty around these findings.

Prediction of Donor Heart Acceptance for Transplant and Its Clinical Implications: Results From The Donor Heart Study.

BACKGROUND: Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction. METHODS: We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130). We identified predictors of acceptance for heart transplant in both cohorts using multivariate logistic regression, incorporating time-interaction terms to characterize their varying effects over time. We fit models predicting acceptance for transplant in a 50% training subset of DHS using logistic regression, least absolute shrinkage and selection operator, and random forest algorithms and compared their performance in the remaining 50% (test) of the subset. RESULTS: Predictors of donor heart acceptance were similar in the nationwide and DHS cohorts. Among these, older age (P value for time interaction, 0.0001) has become increasingly predictive of discard over time while other factors, including those related to drug use, infection, and mild cardiac diagnostic abnormalities, have become less influential (P value for time interaction, <0.05 for all). A random forest model (area under the curve, 0.908; accuracy, 0.831) outperformed other prediction algorithms in the test subset and was used as the basis of a novel web-based prediction tool. CONCLUSIONS: Predictors of donor heart acceptance for transplantation have changed significantly over the last 2 decades, likely reflecting evolving evidence regarding their impact on posttransplant outcomes. Real-time prediction of donor heart acceptance, using our web-based tool, may improve efficiency during donor management and heart allocation.

Mast cell extracellular trap formation underlies vascular and neural injury and hyperalgesia in sickle cell disease.

Sickle cell disease (SCD) is the most common inherited monogenetic disorder. Chronic and acute pain are hallmark features of SCD involving neural and vascular injury and inflammation. Mast cells reside in the vicinity of nerve fibers and vasculature, but how they influence these structures remains unknown. We therefore examined the mechanism of mast cell activation in a sickle microenvironment replete with cell-free heme and inflammation. Mast cells exposed to this environment showed an explosion of nuclear contents with the release of citrullinated histones, suggestive of mast cell extracellular trap (MCET) release. MCETs interacted directly with the vasculature and nerve fibers, a cause of vascular and neural injury in sickle cell mice. MCET formation was dependent upon peptidylarginine deiminase 4 (PAD4). Inhibition of PAD4 ameliorated vasoocclusion, chronic and acute hyperalgesia, and inflammation in sickle mice. PAD4 activation may also underlie neutrophil trap formation in SCD, thus providing a novel target to treat the sequelae of vascular and neural injury in SCD.

Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study.

BACKGROUND: Potential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown. OBJECTIVES: This study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes. METHODS: The Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020. A blinded expert reviewer interpreted all ECGs, which were obtained once hemodynamic stability was achieved after brain death and were repeated 24 ± 6 hours later. ECG findings were summarized, and their associations with other cardiac diagnostic findings, use for HT, and graft survival were assessed using univariable and multivariable regression. RESULTS: Initial ECGs were interpretable for 4,136 potential donors. Overall, 64% of ECGs were deemed clinically abnormal, most commonly as a result of a nonspecific St-T-wave abnormality (39%), T-wave inversion (19%), and/or QTc interval >500 ms (17%). Conduction abnormalities, ectopy, pathologic Q waves, and ST-segment elevations were less common (each present in ≤5% of donors) and resolved on repeat ECGs in most cases. Only pathological Q waves were significant predictors of donor heart nonuse (adjusted OR: 0.39; 95% CI: 0.29-0.53), and none were associated with graft survival at 1 year post-HT. CONCLUSIONS: ECG abnormalities are common in potential heart donors but often resolve on serial testing. Pathologic Q waves are associated with a lower likelihood of use for HT, but they do not portend worse graft survival.

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), [Formula: see text]= 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), [Formula: see text]=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.

Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation.

Vaso-occlusive pain episodes (VOE) cause severe pain in patients with sickle cell disease (SCD). Vaso-occlusive events promote ischemia/reperfusion pathobiology that activates complement. We hypothesized that complement activation is linked to VOE. We used cold to induce VOE in the Townes sickle homozygous for hemoglobin S (HbSS) mouse model and complement inhibitors to determine whether anaphylatoxin C5a mediates VOE. We used a dorsal skinfold chamber to measure microvascular stasis (vaso-occlusion) and von Frey filaments applied to the plantar surface of the hind paw to assess mechanical hyperalgesia in HbSS and control Townes mice homozygous for hemoglobin A (HbAA) mice after cold exposure at 10°C/50°F for 1 hour. Cold exposure induced more vaso-occlusion in nonhyperalgesic HbSS mice (33%) than in HbAA mice (11%) or HbSS mice left at room temperature (1%). Cold exposure also produced mechanical hyperalgesia as measured by paw withdrawal threshold in HbSS mice compared with that in HbAA mice or HbSS mice left at room temperature. Vaso-occlusion and hyperalgesia were associated with an increase in complement activation fragments Bb and C5a in plasma of HbSS mice after cold exposure. This was accompanied by an increase in proinflammatory NF-κB activation and VCAM-1 and ICAM-1 expression in the liver. Pretreatment of nonhyperalgesic HbSS mice before cold exposure with anti-C5 or anti-C5aR monoclonal antibodies (mAbs) decreased vaso-occlusion, mechanical hyperalgesia, complement activation, and liver inflammatory markers compared with pretreatment with control mAb. Anti-C5 or -C5aR mAb infusion also abrogated mechanical hyperalgesia in HbSS mice with ongoing hyperalgesia at baseline. These findings suggest that C5a promotes vaso-occlusion, pain, and inflammation during VOE and may play a role in chronic pain.

Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study.

BACKGROUND: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study. METHODS: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival. RESULTS: An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival. CONCLUSIONS: LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation.

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.

The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease.

In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.

Novel capsaicin cough endpoints effectively discriminate between healthy controls and patients with refractory chronic cough.

RATIONALE: Chronic cough is a common problem, substantially affecting quality of life. Effective treatments and diagnostic clinical tools for refractory chronic cough are lacking which remains a diagnosis of exclusion. OBJECTIVES: To investigate capsaicin evoked cough responses in healthy volunteers and refractory chronic cough patients and assess the discriminatory ability of novel endpoints. METHODS: Dose-response capsaicin cough challenges were performed, and receiver operating characteristic curves constructed to evaluate the discriminatory value of novel endpoints; Emax (maximum number of coughs evoked by any capsaicin concentration) and ED50 (capsaicin concentration evoking at least half of Emax). MEASUREMENTS AND MAIN RESULTS: Ninety-three healthy volunteers (median age 39yrs(IQR; 29-52), 47 females) and 51 refractory chronic cough patients (59yrs(53-67), 31 females) were studied. Emax was significantly higher in the patient group compared to healthy volunteers (p < 0.001) and ED50 was significantly lower (p = 0.001). Both parameters were influenced by gender; females had a higher Emax (p = 0.009) and more sensitive ED50 (p < 0.001) but there were no correlations with other patient demographics. There was a significant relationship between Emax and cough frequency in the patient group (p < 0.001). Emax effectively discriminated between the groups (AUC = 0.83, 95% CI; 0.75-0.90, p < 0.001) independently of ED50 which was less favourable (AUC = 0.66, 95% CI; 0.57-0.76, p = 0.002). Emax and ED50 were shown to be repeatable, and the dose-response method well tolerated. CONCLUSION: Novel capsaicin dose-response endpoints effectively discriminate between healthy controls and refractory chronic cough patients, which may better represent pathophysiological mechanisms and show promise for development as a tool to identify patients with cough hyper-excitability. CLINICAL TRIAL REGISTRATION: www.isrctn.com; ISRCTN23684347.

Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease.

A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are prominent features in patients with sickle cell disease (SCD). Coagulation factor XII (FXII) triggers activation of the contact system that is known to be involved in both thrombosis and inflammation, but not in physiological hemostasis. Therefore, we investigated whether FXII contributes to the prothrombotic and inflammatory complications associated with SCD. We found that when compared with healthy controls, patients with SCD exhibit increased circulating biomarkers of FXII activation that are associated with increased activation of the contact pathway. We also found that FXII, but not tissue factor, contributes to enhanced thrombin generation and systemic inflammation observed in sickle cell mice challenged with tumor necrosis factor α. In addition, FXII inhibition significantly reduced experimental venous thrombosis, congestion, and microvascular stasis in a mouse model of SCD. Moreover, inhibition of FXII attenuated brain damage and reduced neutrophil adhesion to the brain vasculature of sickle cell mice after ischemia/reperfusion induced by transient middle cerebral artery occlusion. Finally, we found higher FXII, urokinase plasminogen activator receptor, and αMß2 integrin expression in neutrophils of patients with SCD compared with healthy controls. Our data indicate that targeting FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that FXII inhibition may provide a safe approach for interference with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.

Sickle red blood cell-derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor.

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.

Factors associated with change in health-related quality of life in people with gout: a 3-year prospective cohort study in primary care.

OBJECTIVE: To describe factors associated with change in health-related quality of life (HRQOL) in people living with gout in primary care. METHODS: In a UK prospective cohort study, adults with a diagnosis of gout registered with 20 general practices completed the Gout Impact Scale (GIS; scale 0-100), 36-item Short Form Physical Function subscale (PF-10; 0-100) and HAQ Disability Index (HAQ-DI; 0-3) via postal questionnaires at baseline and 6, 12, 24 and 36 months. Linear mixed modelling was used to investigate factors associated with changes in HRQOL over 3 years. RESULTS: A total of 1184 participants responded at baseline (adjusted response 65.6%); 990 (83.6%) were male, with a mean age of 65.6 years (s.d. 12.5). A total of 818, 721, 696 and 605 responded at 6, 12, 24 and 36 months, respectively. Factors associated with worse disease-specific and generic HRQOL over 3 years were flare frequency (five or more flares; GIS subscales, PF-10), oligo/polyarticular flares (GIS subscales, PF-10, HAQ-DI), worse pain (GIS subscales, PF-10, HAQ-DI), body pain (GIS subscales, PF-10, HAQ-DI) and more severe depression (GIS subscales, PF-10, HAQ-DI) (P ≤ 0.05). More severe anxiety was associated with worse disease-specific HRQOL only (GIS subscales). Older age (PF-10), being female (PF-10, HAQ-DI) and BMI (HAQ-DI) were associated with worse generic HRQOL (P ≤ 0.05). CONCLUSION: Gout-specific, comorbid and sociodemographic factors were associated with change in HRQOL over a 3-year period, highlighting people at risk of worse outcomes who could be targeted for interventions.

Monitoring residual kidney function in haemodialysis patients using timed urine collections: validation of the use of estimated blood results to calculate GFR.

Objective. With growing recognition of the benefits of preserving residual kidney function (RKF) and use of incremental treatment regimes, the incentive to measure residual clearance in haemodialysis patients is increasing. Interdialytic urine collections used to monitor RKF in research studies are considered impractical in routine care, partly due to the requirement for blood samples before and after the collection. Plasma solute levels can be estimated if patients are in 'steady state', where urea and creatinine concentrations increase at a constant rate between dialysis sessions and are reduced by a constant ratio at each session. Validation of the steady state assumption would allow development of simplified protocols for urine collections in HD patients.Approach. Equations were derived for estimating plasma urea and creatinine at the start or end of the interdialytic interval for patients in steady state. Data collected during the BISTRO study was used to assess the agreement between measured and estimated plasma levels and the effect of using estimated levels on the calculated glomerular filtration rate (GFR).Main results. The mean difference between GFR calculated with estimated plasma levels for the HD session after the collection and a full set of measured levels was 2.0% (95% limits of agreement -10.7% to +14.7%,N = 316). Where plasma levels for the session before the collection were estimated, the mean difference was 1.2% (limits of agreement -10.3% to +7.9%,N = 275).Significance. Using estimated levels for one session led to a clinically significant difference in the calculated GFR for less than 3% of the collections studied. This indicates that the steady state assumption can be used to estimate solute levels when determining GFR from timed urine collections. A pragmatic approach to monitoring RKF in HD would be for patients to collect for approximately 24 h before routine bloods are taken.

MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease.

Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely elucidated. Ischemia-reperfusion and heme released from hemoglobin during hemolysis, events that characterize SCD pathophysiology, can activate the lectin pathway (LP) and alternative pathway (AP), respectively. Here we evaluated the role of LP and AP in Townes sickle (SS) mice using inhibitory monoclonal antibodies (mAb) to mannose binding lectin (MBL)-associated serine protease (MASP)-2 or MASP-3, respectively. Townes SS mice were pretreated with MASP-2 mAb, MASP-3 mAb, isotype control mAb, or PBS before they were challenged with hypoxia-reoxygenation or hemoglobin. Pretreatment of SS mice with MASP-2 or MASP-3 mAb, markedly reduced Bb fragments, C4d and C5a in plasma and complement deposition in the liver, kidneys, and lungs collected 4 hours after challenge compared to control mAb-treated mice. Consistent with complement inhibition, hepatic inflammation markers NF-ĸB phospho-p65, VCAM-1, ICAM-1, and E-selectin were significantly reduced in SS mice pretreated with MASP-2 or MASP-3 mAb. Importantly, MASP-2 or MASP-3 mAb pretreatment significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients.

Challenges encountered in conducting donor-based research: Lessons learned from the Donor Heart Study.

Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80-102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.