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.

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.

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.

[This corrects the article DOI: 10.1093/ckj/sfz038.].

Implementation of a frailty screening programme and Geriatric Assessment Service in a nephrology centre: a quality improvement project.

INTRODUCTION: The aims of this quality improvement project were to: (1) proactively identify people living with frailty and CKD; (2) introduce a practical assessment, using the principles of the comprehensive geriatric assessment (CGA), for people living with frailty and chronic kidney disease (CKD) able to identify problems; and (3) introduce person-centred management plans for people living with frailty and CKD. METHODS: A frailty screening programme, using the Clinical Frailty Scale (CFS), was introduced in September 2018. A Geriatric Assessment (GA) was offered to patients with CFS ≥ 5 and non-dialysis- or dialysis-dependent CKD. Renal Frailty Multidisciplinary Team (MDT) meetings were established to discuss needs identified and implement a person-centred management plan. RESULTS: A total of 450 outpatients were screened using the CFS. One hundred and fifty patients (33%) were screened as frail. Each point increase in the CFS score was independently associated with a hospitalisation hazard ratio of 1.35 (95% CI 1.20-1.53) and a mortality hazard ratio of 2.15 (95% CI 1.63-2.85). Thirty-five patients received a GA and were discussed at a MDT meeting. Patients experienced a median of 5.0 (IQR 3.0) problems, with 34 (97%) patients experiencing at least three problems. CONCLUSIONS: This quality improvement project details an approach to the implementation of a frailty screening programme and GA service within a nephrology centre. Patients living with frailty and CKD at risk of adverse outcomes can be identified using the CFS. Furthermore, a GA can be used to identify problems and implement a person-centred management plan that aims to improve outcomes for this vulnerable group of patients.

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.

[This corrects the article DOI: 10.1093/ckj/sfz038.].

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, multicomponent home-based exercise programme in prefrail 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 prefrail or frail, following Frailty Phenotype (FP) 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. Semistructured 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 (FP), 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 aims to publish findings in a peer-reviewed journal and presents 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. TRIAL REGISTRATION NUMBER: ISRCTN87708989.

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.

Background: Understanding how frailty affects health-related quality of life (HRQOL) in those with chronic kidney disease (CKD) could assist in the development of management strategies to improve outcomes for this vulnerable patient group. This study aimed to evaluate the relationship between frailty and HRQOL in patients with CKD Stages 4 and 5 (G4­5) and those established on haemodialysis (G5D). Methods: Ninety participants with chronic kidney disease (CKD G4­5D) were recruited between December 2016 and December 2017. Frailty was assessed using the Frailty Phenotype, which included assessments of unintentional weight loss, weakness (handgrip strength), slowness (walking speed), physical activity and self-perceived exhaustion. HRQOL was assessed using the RAND 36-Item Health Survey Version 1.0 (SF-36). Results: Nineteen (21%) patients were categorized as frail. Frailty, when adjusted for age, gender, dialysis dependence and comorbidity, had a significant effect on five of the eight SF-36 domains: physical functioning, role limitations due to emotional problems, energy/fatigue, social functioning and pain. Regression modelling best explained the variation in the physical functioning domain (adj. R2 = 0.27, P < 0.001), with frailty leading to a 26-point lower score. Exhaustion was the only Frailty Phenotype component that had a significant effect on scores across all SF-36 domains. Conclusions: Frailty is independently associated with worse HRQOL in patients with CKD G4­5D, with self-perceived exhaustion being the most significant Frailty Phenotype component contributing to HRQOL. Efforts should be made to identify frail patients with CKD so that management strategies can be offered that aim to improve morbidity, mortality and patient-reported outcomes, including HRQOL and fatigue.

Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development.

Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.