Andrew McClean

The characterisation and determinants of quality of life in ANCA associated vasculitis

Objectives To contextualise and identify the determinants of poor health related quality of life (QOL) among patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). Methods A multicentre AAV case–control study was conducted using two matched groups of population and chronic disease controls. Measures of physical and mental QOL as well as putative bio-psychosocial determinants of QOL impairment were collected. Concurrently, putative clinical QOL determinants were recorded. Conditional logistic regression analyses characterised group differences while multivariable logistic regression identified within-case QOL associations which were further quantified using population attributable risks (PAR). Results Cases (n=410) experienced similar QOL to chronic disease controls (n=318) (physical QOL: OR 0.7, 95% CI 0.4 to 1.1; mental QOL: OR 1.1, 95% CI 0.8 to 1.6). However, they were substantially more likely to report poor QOL compared to general population controls (n=470) (physical QOL: OR 7.0, 95% CI 4.4 to 11.1; mental QOL: OR 2.5, 95% CI 1.7 to 3.6). A few clinical, but many more bio-psychosocial factors were independently associated with poor QOL. In population terms, fatigue was found to be of principal importance (physical QOL: PAR 24.6%; mental QOL: PAR 47.4%). Conclusions AAV patients experienced significant QOL impairment compared to the general population, but similar to those with other chronic diseases whose considerable needs are already recognised. Potentially modifiable clinical determinants have been identified; however bio-psychosocial interventions are likely to provide the greater QOL gains in this patient population.

Assessing and comparing rival definitions of delayed renal allograft function for predicting subsequent graft failure.

Background. The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and “functional” definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF. Methods. We studied 750 adult deceased donor kidney transplant recipients (1996–2006) and analyzed the association between these two DGF definitions and long-term graft outcome. Results. Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16–2.18; P=0.004 and HR 1.72; 95% CI 1.26–2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03–2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06–2.03; P=0.02). Results were similar for overall graft failure. Conclusions. This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint.

Explaining fatigue in ANCA-associated vasculitis

OBJECTIVES To identify the determinants of fatigue among patients with ANCA-associated vasculitis (AAV). METHODS A multicentre cross-sectional study was conducted. Subjects fulfilling the European Medicines Agency criteria for granulomatosis with polyangiitis (Wegeners), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) were approached according to consecutive clinic attendance and invited to complete a questionnaire assessing fatigue and putative biopsychosocial determinants of this symptom. Concurrently, potential clinical determinants were recorded. Independent associations of fatigue were identified using forward stepwise logistic regression modelling and their overall impact expressed as population attributable risk (PAR). RESULTS The majority (74.8%) of participants (n = 410) reported high levels of fatigue that were found to be significantly associated with numerous biopsychosocial and clinical factors. Sleep disturbance [odds ratio (OR) 5.3, 95% CI 2.7, 10.5] and pain (OR 3.8, 95% CI 2.0, 7.3) were the strongest independent associations of fatigue and, on a population level, each was more than twice as important as any other putative determinant (PAR 18.1% and 16.5%, respectively). Female gender (OR 2.1, 95% 1.1, 4.0), elevated CRP (OR 3.7, 95% CI 1.7, 8.1) and the dysfunctional coping strategies of behavioural disengagement (OR 2.4, 95% CI 1.04, 5.6) and denial (OR 2.4, 95% CI 0.9, 6.7) were also independently associated with fatigue. CONCLUSION The data suggest that AAV-related fatigue is multifactorial in origin. Sleep disturbance and pain were found to be most important, although inflammation, as measured by CRP, was also associated. This study has identified potentially modifiable determinants that will inform future interventions aimed at alleviating fatigue.

Predictors and consequences of fatigue in prevalent kidney transplant recipients.

Background Fatigue has been underinvestigated in stable kidney transplant recipients (KTRs). The objectives of this study were to investigate the nature, severity, prevalence, and clinical awareness of fatigue in medically stable KTRs, examine the impact of fatigue on quality of life (QoL), and explore the underlying causes of posttransplantation fatigue. Methods This single-center cross-sectional study enrolled 106 stable KTRs. Multi-dimensional Fatigue Inventory-20 was used to measure five fatigue dimensions: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue. Clinical awareness of fatigue was determined by reviewing medical records. QoL was assessed by Medical Outcomes Study Short Form-36 Questionnaire. Demographic, clinical, psychosocial, and behavioral parameters were evaluated as fatigue predictors. Results Fatigue was found in 59% of KTRs. Only 13% had this symptom documented in medical records. Fatigue in KTRs was in the same range as chronically unwell patients, with Physical Fatigue, Reduced Activity, and Reduced Motivation approached levels observed in chronic fatigue syndrome. All fatigue dimensions significantly and inversely correlated with QoL (P<0.001 for all associations). Demographic predictors were male, older age, and non-Caucasian ethnicity (P⩽0.05 for all associations). Clinical predictors included elevated highly sensitive C-reactive protein (inflammation), decreased estimated glomerular filtration rate (graft dysfunction), and reduced lean tissue index (P⩽0.05 for all associations). Psychosocial and behavioral predictors were inferior sleep quality, anxiety, and depression (P<0.01 for all associations). Conclusions Fatigue is common and pervasive in clinically stable KTRs. It is strongly associated with reduced QoL. This study identified modifiable fatigue predictors and sets the scene for future interventional studies.

Markers for work disability in anti-neutrophil cytoplasmic antibody-associated vasculitis

OBJECTIVES ANCA-associated vasculitis (AAV) commonly affects those of working age. Since survival rates have been transformed by immunotherapeutics, the measurement of other outcomes has become increasingly relevant. Work disability is an important outcome for both patient and society that has yet to be fully evaluated in AAV. We aimed to assess employment status in AAV patients and identify putative predictors of their work disability. METHODS A cross-sectional study was undertaken. AAV cases were recruited according to consecutive clinic attendance. Subjects completed a questionnaire that determined employment status and other psychosocial measures. Clinical factors were concurrently recorded by the attending physician. From the data of those subjects of working age, a multivariable model was developed using forward stepwise logistic regression to identify the independent associations of work disability, defined by those subjects reporting unemployment secondary to ill-health. Results are expressed as odds ratios (ORs) and 95% CIs. RESULTS Of the 410 participants (84.4% response rate), 149 (36.7%) were employed, 197 (48.6%) retired and 54 (13.3%) unemployed secondary to ill health. Of those of working age, 26.0% were considered work disabled. Fatigue (OR 7.1, 95% CI 1.5, 33.1), depression (OR 4.4, 95% CI 1.8, 10.8), severe disease damage [Vasculitis Damage Index (VDI) > 4 (OR 3.9, 95% CI 1.01, 14.7)] and being overweight (OR 3.4, 95% CI 1.3, 8.9) were independently associated with their unemployment. CONCLUSION A quarter of working-age AAV subjects reported unemployment as a result of ill health and are characterized by high levels of fatigue, depression, disease damage and being overweight. These potentially modifiable factors may inform future multidisciplinary interventions aimed at alleviating work disability.

Cardiovascular, Muscular and Perceptual Contributions to Physical Fatigue in Prevalent Kidney Transplant Recipients

Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single‐centre observational cross‐sectional study enrolled 55 KTRs. Muscle mass was quantified using dual‐energy x‐ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age‐adjusted Borg scale‐ratings. Physical fatigue was measured using Multi‐Dimensional Fatigue Inventory‐20. QoL was assessed using Medical Outcomes Study Short Form‐36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions.

The role of hepcidin-25 in kidney transplantation

Background Hepcidin-25 is a peptide hormone involved in iron absorption and homeostasis and found at increased serum levels in conditions involving systemic inflammation, renal dysfunction, and increased adiposity. Hepcidin may play a role in the pathogenesis of anemia, but its role in kidney transplantation is undefined. Methods This study enrolled 100 stable patients beyond 12 months after transplantation, from a large single United Kingdom center. Serum hepcidin-25 level, and relevant demographic and laboratory data pertinent to posttransplantation anemia, were measured and collected. Independent predictors of serum hepcidin were evaluated, and the relationship between hepcidin and hemoglobin, assessed. Results Independent associations were seen between higher hepcidin levels and allograft dysfunction (estimated glomerular filtration rate), increased inflammation (high-sensitivity C-reactive peptide), higher transferrin saturation (a marker of iron stores), and the use of marrow-suppressive medication (P<0.05 for all). Higher fat tissue index (whole-body multifrequency bioimpedance measurement) was also associated with higher hepcidin levels, but this relationship did not persist after adjustment for inflammation (high-sensitivity C-reactive peptide). In turn, inflammation was associated with increased fat tissue index (P=0.01) and male gender (P=0.04). A nonlinear association between serum hepcidin level and hemoglobin was seen, with a progressive fall in hemoglobin as hepcidin levels rose to 100 ng/mL, but little effect thereafter (P=0.009). This association was independent of renal dysfunction and female gender, both of which were also independently associated with a lower hemoglobin level. Conclusions These results highlight possible mechanisms of hemoglobin reduction in kidney transplantation patients, and the therapeutic opportunities from understanding the role of hepcidin in this context.

Physical Fatigue, Fitness and Muscle Function in Patients with Anti‐neutrophil Cytoplasm Antibody‐Associated Vasculitis

This study investigated differences in cardiorespiratory fitness, muscular function, perceived exertion, and anxiety/depression between patients and healthy controls (HCs) and assessed which of these variables may account for the fatigue experienced by patients.

CONTEXTUALISING QUALITY OF LIFE IN ANCA ASSOCIATED VASCULITIS (AAV)

Background Impaired quality of life (QOL) is of universal relevance and not just confined to the unhealthy. Although existing data demonstrates poor QOL amongst patients with AAV, it is essential to contextualise these reports with both general and other diseased populations in order to fully ascertain the scale of the problem. Thus far, studies have only made retrospective comparisons with unmatched populations using different methodologies. Furthermore, study sample sizes have been sufficient to quantify only the largest of differences. Objectives This large study aimed to quantify QOL in AAV patients compared to matched general and disease control populations. Methods A multi-centre case-control study using two groups of a) population and b) disease controls. AAV cases were recruited from rheumatology and renal departments across the UK. For each participating case, general population controls were identified from a commercial on-line sampling frame (>80% population coverage). They were matched according to age, sex and postcode. In addition, disease controls were invited, matched according to age, sex and department. Cases recruited from rheumatology departments were matched to patients with inflammatory arthritis while those recruited from renal departments were matched to patients with non-inflammatory chronic kidney disease, reflecting a typical clinic attendee from the respective specialty. All cases and controls completed a questionnaire which combined recognised measures of QOL. Specific instruments assessed physical and mental health status (SF36), sleep disturbance (Estimation of sleep problems questionnaire) and fatigue (Chalder Fatigue Scale).The scores of these were dichotomised into high and low categories by the mean of the population controls. In addition, anxiety and depression was defined using the Hospital Anxiety and Depression Scale (HADS) and data collected on employment status. Cases were compared to controls using conditional logistic regression and results expressed as odds ratios (OR). Results 410 cases were identified from 11 centres, with 470 population and 318 disease controls. Cases reported significantly poorer QOL than population controls across all domains. Compared to controls, cases were substantially more likely to report low physical and mental health respectively (OR 7.0,95%CI 4.4-11.1 and OR 2.5,95%CI 1.7-3.6). In addition they were much more likely to be unemployed due to their health (OR 6.9,95%CI 3.0-15.8), report high fatigue (OR 4.1,95%CI 2.7-6.3), feel depressed (OR 4.3,95%CI 2.4-7.5), endure sleep disturbance (OR 2.1, 95%CI 1.5-2.9) and suffer anxiety (OR 1.6,95%CI 1.1-2.3). Across all domains, cases reported no significant differences in QOL compared to disease controls. Conclusions Compared with the general population, AAV patients experienced significantly impaired QOL. QOL levels were as poor as those reported by typical rheumatology and renal clinic attendees whose considerable needs are already well established. Disclosure of Interest None Declared

Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease

Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.