Comparing outcomes of biopsy-proven anti-neutrophil cytoplasmic autoantibody–associated glomerulonephritis patients treated with cyclophosphamide in the 20th and 21st centuries: a 23-year study

Background Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disorder associated with significant morbidity and mortality. Approximately 80–90% of patients have circulating ANCAs. Long-term outcomes appear to be improving. This retrospective study analyses the incidence and patient outcomes over a period of 23 years at a single tertiary centre. Methods Outcomes of patients diagnosed with AAV between 1 January 1988 and 31 December 2010 were collected retrospectively. Data including patient demographics, age of diagnosis, dates of starting renal replacement therapy, death and biochemistry results were collected. Patients were divided into two cohorts (1988–99 and 2000–10) and analysed using Stata software (StataCorp, College Station, TX, USA). Results A complete dataset was obtained for 273 patients. Of these patients, 101 were diagnosed between 1988 and 1999 while 172 were diagnosed between 2000 and 2010. The number of patients diagnosed with AAV increased from 2.2/million in 1988 to 10.3/million in 2010. A higher proportion of patients (56.4%) in the earlier cohort presented with creatinine >500 μmol/L compared with the later cohort (30.2%; P < 0.001). Overall patient survival improved significantly between the two cohorts. Cohort 1 had a median survival of 59 months compared with 125 months for Cohort 2 (P = 0.003). Conclusions This study shows that AAV is being diagnosed at an earlier stage, resulting in improved outcomes. This may be because of improvements in the management of AAV and chronic kidney disease

Glucocorticoid therapy in ANCA Vasculitis - using the Glucocorticoid Toxicity Index as an outcome measure

Background Anti-neutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV) is an autoimmune disease. Induction remission and maintenance treatment typically includes high dose, tapering glucocorticoids (GC) in addition to other immunosuppressive medication. The use of Glucocorticoid Toxicity Index (GTI), provides a global, quantifiable assessment tool in which clinicians can assess GC associated morbidity. Recent trials in AAV have exposed the need for systemic assessment of GC burden. In this small cohort study, we look to address these issues and the justification of newer GC sparing agents such as C5a inhibitors. Methods A retrospective cohort study of 43 patients with biopsy AAV was constructed from a single centre between 2012 to 2016 and followed up for 48 months. The GTI table made up of adverse features used to quantify patients GC toxicity. Electronic patient records were reviewed and scores calculated according to published methods. GTI scores were compared with cumulative steroid doses at separate intervals as well as incidences of adverse features in relation to the treatment timeline. Results The mean age was 65.9 (± 11.06) years and treatment regimens consisted of glucocorticoids alongside cyclophosphamide or rituximab. Our results showed statistical significance in the association of cumulative GC doses and GTI scores (p=0.008, 95% CI, 1.31 to 8.05). Adverse features relating to mood disturbance and GC induced psychosis occurred early, in contrast to adrenal insufficiency which typically presented later in the follow up. Infection related adverse events were consistent throughout. Conclusions We demonstrated that higher, cumulative doses of steroids in AAV lead to worse glucocorticoid related toxicity. Using the GTI creates potential to individualise and quantify the adverse effects patients experience as a result of GC treatment and permits more patient centred management. Whilst glucocorticoids remain the main adjunctive immunosuppression of AAV treatment, the narrow therapeutic window supports the need for GC-sparing treatments

Diagnostic Accuracy of Frailty Screening Methods in Advanced Chronic Kidney Disease

BACKGROUND/AIMS: Frail patients with chronic kidney disease (CKD) have an increased hospitalisation and mortality rate. However, many popular frailty screening methods have not been validated in patients with CKD. This study evaluates the diagnostic accuracy of several frailty screening methods in patients with CKD G4-5 and those established on haemodialysis (G5D). METHODS: Ninety participants with CKD G4-5D were recruited from Nephrology Outpatient Clinics and 2 Haemodialysis Units between December 2016 and December 2017. Frailty was diagnosed using the Fried Frailty Phenotype. The following frailty screening tests were evaluated: Clinical Frailty Scale, PRISMA-7, CKD Frailty Index, CKD FI-LAB, walking speed, hand grip strength and Short Physical Performance Battery. RESULTS: The mean age of participants was 69 years (SD ±13). One-third of participants were dialysis-dependent. Nineteen (21%) patients were categorised as frail, 42 (47%) as pre-frail and 29 (32%) as robust. Overall, walking speed was the most discriminative measure (AUC 0.97 [95% CI 0.93-1.00], sensitivity 0.84 [95% CI 0.62-0.94], specificity 0.96 [95% CI 0.88-0.99]). The Clinical Frailty Scale had the best performance of the non-physical assessment frailty screening methods (AUC 0.90 [95% CI 0.84-0.97], sensitivity 0.79 [95% CI 0.57-0.91], specificity 0.87 [95% CI 0.78-0.93]). CONCLUSIONS: Walking speed can be used to accurately screen for frailty in CKD populations. If it is not practical to perform a physical assessment to screen for frailty, the Clinical Frailty Scale is a useful alternative

Erratum: Frailty is independently associated with worse health-related quality of life in chronic kidney disease: a secondary analysis of the Frailty Assessment in Chronic Kidney Disease study

In the original article, in the ‘Methods’ section of the abstract, there were some incorrect words added. It originally read ‘Ninety participants with dialysis-dependent chronic kidney disease (CKD G4–5D) were recruited between December 2016 and December 2017’- the words ‘dialysis-dependent’ have been removed. The Publisher apologizes for the error

The EX-FRAIL CKD Trial: a study protocol for a pilot randomised controlled trial of a home-based EXercise programme for pre-FRAIL and FRAIL, older adults with Chronic Kidney Disease

Introduction Frailty is highly prevalent in adults with chronic kidney disease (CKD) and is associated with adverse health outcomes including falls, poorer health-related quality of life (HRQOL), hospitalisation and mortality. Low physical activity and muscle wasting are important contributors to physical frailty in adults with CKD. Exercise training may improve physical function and frailty status leading to associated improvements in health outcomes, including HRQOL. The EX-FRAIL CKD trial aims to inform the design of a definitive randomised controlled trial (RCT) that investigates the effectiveness of a progressive, multi-component home-based exercise programme in pre-frail and frail older adults with CKD. Methods and Analysis The EX-FRAIL CKD trial is a two-arm parallel group pilot RCT. Participants categorised as pre-frail or frail, following Frailty Phenotype assessment, will be randomised to receive exercise or usual care. Participants randomised to the intervention arm will receive a tailored 12-week exercise programme, which includes weekly telephone calls to advise on exercise progression. Primary feasibility outcome measures include rate of recruitment, intervention adherence, outcome measure completion and participant attrition. Semi-structured interviews with a purposively selected group of participants will inform the feasibility of the randomisation procedures, outcome measures and intervention. Secondary outcome measures include physical function (walking speed and Short Physical Performance Battery), frailty status (Frailty Phenotype), fall concern (Falls Efficacy Scale-International tool), activities of daily living (Barthel Index), symptom-burden (Palliative Care Outcome Scale-Symptoms RENAL) and HRQOL (Short Form-12v2). Ethics and Dissemination Ethical approval was granted by a National Health Service (NHS) Regional Ethics Committee and the NHS Health Research Authority. The study team aim to publish findings in a peer-reviewed journal and present the results at relevant national and international conferences. A summary of findings will be provided to participants, a local kidney patient charity and the funding body

Automated Computational Detection of Disease Activity in ANCA-Associated Glomerulonephritis Using Raman Spectroscopy: A Pilot Study

Biospectroscopy offers the ability to simultaneously identify key biochemical changes in tissue associated with a given pathological state to facilitate biomarker extraction and automated detection of key lesions. Herein, we evaluated the application of machine learning in conjunction with Raman spectroscopy as an innovative low-cost technique for the automated computational detection of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Consecutive patients with active AAGN and those in disease remission were recruited from a single UK centre. In those with active disease, renal biopsy samples were collected together with a paired urine sample. Urine samples were collected immediately prior to biopsy. Amongst those in remission at the time of recruitment, archived renal tissue samples representative of biopsies taken during an active disease period were obtained. In total, twenty-eight tissue samples were included in the analysis. Following supervised classification according to recorded histological data, spectral data from unstained tissue samples were able to discriminate disease activity with a high degree of accuracy on blind predictive modelling: F-score 95% for >25% interstitial fibrosis and tubular atrophy (sensitivity 100%, specificity 90%, area under ROC 0.98), 100% for necrotising glomerular lesions (sensitivity 100%, specificity 100%, area under ROC 1) and 100% for interstitial infiltrate (sensitivity 100%, specificity 100%, area under ROC 0.97). Corresponding spectrochemical changes in paired urine samples were limited. Future larger study is required, inclusive of assigned variables according to novel non-invasive biomarkers as well as the application of forward feature extraction algorithms to predict clinical outcomes based on spectral features

Home-based exercise for people living with frailty and chronic kidney disease: A mixed-methods pilot randomised controlled trial

Background: Frailty is associated with adverse health outcomes in people with chronic kidney disease (CKD). Evidence supporting targeted interventions is needed. This pilot randomised controlled trial (RCT) aimed to inform the design of a definitive RCT evaluating the effectiveness of a home-based exercise intervention for pre-frail and frail older adults with CKD. Methods: Participants were recruited from nephrology outpatient clinics to this two-arm parallel group mixed-methods pilot RCT. Inclusion criteria were: ≥65 years old; CKD G3b-5; and Clinical Frailty Scale score ≥4. Participants categorised as pre-frail or frail using the Frailty Phenotype were randomised to a 12-week progressive multi-component home-based exercise programme or usual care. Primary outcome measures included eligibility, recruitment, adherence, outcome measure completion and participant attrition rate. Semi-structured interviews were conducted with participants to explore trial and intervention acceptability. Results: Six hundred and sixty-five patients had an eligibility assessment with 217 (33%; 95% CI 29, 36) eligible. Thirty-five (16%; 95% CI 12, 22) participants were recruited. Six were categorised as robust and withdrawn prior to randomisation. Fifteen participants were randomised to exercise and 14 to usual care. Eleven (73%; 95% CI 45, 91) participants completed ≥2 exercise sessions/week. Retained participants completed all outcome measures (n = 21; 100%; 95% CI 81, 100). Eight (28%; 95% CI 13, 47) participants were withdrawn. Fifteen participated in interviews. Decision to participate/withdraw was influenced by perceived risk of exercise worsening symptoms. Participant perceived benefits included improved fitness, balance, strength, well-being, energy levels and confidence. Conclusions: This pilot RCT demonstrates that progression to definitive RCT is possible provided recruitment and retention challenges are addressed. It has also provided preliminary evidence that home-based exercise may be beneficial for people living with frailty and CKD. Trial registration: ISRCTN87708989; https://clinicaltrials.gov/

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy

Abstract: The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment