Cardioverting acute atrial fibrillation and the risk of thromboembolism: not all patients are created equal

Current guidelines support the well-established clinical practice that patients who present with atrial fibrillation (AF) of less than 48 hours duration should be considered for cardioversion, even in the absence of pre-existing anticoagulation. However, with increasing evidence that short runs of AF confer significant risk of stroke, on what evidence is this 48-hour rule based and is it time to adopt a new approach? We review existing evidence and suggest a novel approach to risk stratification in this setting. Overall, the risk of thromboembolism associated with acute cardioversion of patients with AF that is estimated to be of <48 hours duration is low. However, this risk varies widely depending on patient characteristics. From existing evidence, we show that using the CHA2DS2-VASc score may allow better selection of appropriate patients in order to prevent exposing specific patient groups to an unacceptably high risk of a potentially devastating complication

Auscultating heart and breath sounds through patients’ gowns: who does this and does it matter?

Background Doctors are taught to auscultate with the stethoscope applied to the skin, but in practice may be seen applying the stethoscope to the gown. Objectives To determine how often doctors auscultate heart and breath sounds through patients’ gowns, and to assess the impact of this approach on the quality of the sounds heard. Methods A sample of doctors in the west of Scotland were sent an email in 2014 inviting them to answer an anonymous questionnaire about how they auscultated heart and breath sounds. Normal heart sounds from two subjects were recorded through skin, through skin and gown, and through skin, gown and dressing gown. These were played to doctors, unaware of the origin of each recording, who completed a questionnaire about the method and quality of the sounds they heard. Results 206 of 445 (46%) doctors completed the questionnaire. 124 (60%) stated that they listened to patients’ heart sounds, and 156 (76%) to patients’ breath sounds, through patients’ gowns. Trainees were more likely to do this compared with consultants (OR 3.39, 95% CI 1.74 to 6.65). Doctors of all grades considered this practice affected the quality of the sounds heard. 32 doctors listened to the recorded heart sounds. 23 of the 64 (36%) skin and 23 of the 64 (36%) gown recordings were identified. The majority of doctors (74%) could not differentiate between skin or gown recordings, but could tell them apart from the double layer recordings (p=0.02). Trainees were more likely to hear artefactual added sounds (p=0.04). Conclusions Many doctors listen to patients’ heart and breath sounds through hospital gowns, at least occasionally. In a short test, most doctors could not distinguish between sounds heard through a gown or skin. Further work is needed to determine the impact of this approach to auscultation on the identification of murmurs and added sounds

Functional magnetic resonance imaging in patients with kidney failure: optimising imaging biomarkers

Introduction: The prevalence of kidney failure is increasing globally. Patients with kidney failure experience a vastly increased risk of cardiovascular disease and premature death, which is incompletely offset with current kidney replacement therapies. The development of reliable biomarkers in kidney failure could allow novel therapeutics to be more readily trialled in patients with kidney failure due to enhanced patient selection, reduced participant burden and reduced trial duration and cost. The present thesis utilises 6 distinct studies to examine imaging biomarkers applied to 2 sub-populations of patients with kidney failure. Firstly, I explore several imaging techniques assessing the excess cardiovascular risk observed in patients on dialysis (studies 1-4). Secondly, I examine the utility of renal MRI to investigate kidney transplant dysfunction (studies 5, 6). Methods and Results: 1. Global longitudinal strain on cardiovascular MRI. In a retrospective study of 215 participants with kidney failure, left ventricular global longitudinal strain on cardiovascular MRI associated with all-cause mortality, independent of baseline clinical variables and future renal transplantation. 2. Effect of haemodialysis on native T1 mapping. In a prospective study of 26 patients undergoing regular haemodialysis, acute changes in cardiac volumes and myocardial composition were detectable on 3T cardiovascular MRI following a single session of haemodialysis with fluid removal. 3. Radial-VIBE MRI for the detection of vascular calcification. In a prospective study of 96 individuals with kidney failure (24 haemodialysis, 72 transplant), a radialVIBE sequence on MRI was subjectively able to detect thoracic aortic calcification. However, significant bias existed with respect to quantification of calcification volume, with MRI over-estimating volume when minimal calcification was present and under-estimating it at greater volumes. Improvements in radial-VIBE image quality are necessary, and until then CT should remain the primary modality for assessing vascular calcification in clinical practice. 4. Myocardial extracellular volume by contrast enhanced CT. In a prospective study of 23 participants on regular haemodialysis there was no correlation between extracellular volume on CT and myocardial native T1 (a surrogate for myocardial fibrosis). 5. Different regions of interest for the analysis of multiparametric renal MRI. In a pooled study consisting of 40 participants (10 healthy volunteers, 10 patients with left ventricular systolic dysfunction and 20 renal transplant recipients) comparing different regions of interest (ROI) for the analysis of renal MRI, it was found that manually drawn ROIs delineating the cortex or in a representative area of cortex could be used interchangeably, with acceptable inter-observer reproducibility. 6. Multiparametric renal MRI for the investigation of renal transplant dysfunction. In a study of 28 participants (20 with complete data) that was stopped prematurely due to the COVID-19 pandemic, there was no correlation between any renal MRI variable and the percentage of renal cortex containing fibrosis. Conclusion: There is a clear clinical need for the development and validation of reliable biomarkers for patients with kidney failure. However, the results of the present thesis suggest that, in their present form, neither functional MRI for the identification of cardiovascular disease in patients undergoing dialysis, nor renal MRI in patients with transplant dysfunction, are ready for implementation into clinical trial research protocols or clinical practice

Assessment of active tubulointerstitial nephritis in non-scarred renal cortex improves prediction of renal outcomes in patients with IgA nephropathy

Background: The addition of tubulointerstitial inflammation to the existing pathological classification of IgA nephropathy (IgAN) is appealing but was previously precluded due to reportedly wide inter-observer variability. We report a novel method to score percentage of non-atrophic renal cortex containing active tubulointerstitial inflammation (ATIN) in patients with IgAN and assess its utility to predict clinical outcomes. Methods: All adult patients with a native renal biopsy diagnosis of IgAN between 2010 and 2015 in a unit serving 1.5 million people were identified. Baseline characteristics, biopsy reports and outcome data were collected. ATIN was calculated by subtracting the percentage of atrophic cortex from the percentage of total cortex with tubulointerstitial inflammation, with ≥10% representing significant ATIN. The primary outcome was a composite of requiring renal replacement therapy or doubling of serum creatinine. Results: In total 153 new cases of IgAN were identified, of which 111 were eligible for inclusion. Of these, 76 (68%) were male and 54 (49%) had ATIN on biopsy. During a median follow-up of 2.3 years, 34 (31%) reached the primary outcome. On univariable Cox regression analysis, ATIN was associated with a five-fold increase in the primary outcome [hazard ratio (HR) (95% confidence interval) 4.9 (95% confidence interval (CI) 2.1–11.3)]. On multivariable analysis, mesangial hypercellularity, tubular atrophy and interstitial fibrosis and ATIN independently associated with renal outcome (P = 0.02 for ATIN). Inter-observer reproducibility revealed fair agreement in the diagnosis of ATIN (κ=0.43, P = 0.05). Conclusions: Within our centre, ATIN was significantly associated with renal outcome in patients with IgAN, independently of established histological features and baseline clinical characteristics

Associations between multimorbidity and adverse clinical outcomes in patients with chronic kidney disease: a systematic review and meta-analysis

Objective: To systematically review the literature exploring the associations between multimorbidity (the presence of two or more long term conditions (LTCs)) and adverse clinical outcomes in patients with chronic kidney disease (CKD). Design: Systematic Review and Meta-analysis. Data sources: MEDLINE, EMBASE, CINAHL, Cochrane Library and SCOPUS (1946-2019). The main search terms were “Chronic Kidney Failure” and “Multimorbid*”. Eligibility Criteria: Observational studies of adults over the age of 18 with CKD stages three to five i.e. eGFR less than 60ml/minute/1.73m2. The exposure was Multimorbidity quantified by Measures and the outcomes were all-cause mortality, renal progression, hospitalisation and cardiovascular events. We did not consider CKD as a co-morbid LTC. Data Extraction and Synthesis: Newcastle Ottawa Scale for quality appraisal and risk of bias assessment and fixed-effects meta-analysis for data synthesis. Results: Of 1852 papers identified, 26 met the inclusion criteria. 21 papers involved patients with advanced CKD and no studies were from low or middle income countries. All-cause mortality was an outcome in all studies. Patients with multimorbidity were at higher risk of mortality compared to patients without multimorbidity (Total risk ratio 2.28 (95% confidence interval 1.81-2.88)). The risk of mortality was higher with increasing multimorbidity (Total hazard ratio 1.31 (1.27-1.36)) and both concordant and discordant LTCs were associated with heightened risk. Multimorbidity was associated with renal progression in four studies, hospitalisation in five studies and cardiovascular events in two studies. Limitations: Meta-analysis could only include 10 of 26 papers as the methodologies of studies were heterogeneous. Conclusions: There are associations between multimorbidity and adverse clinical outcomes in patients with CKD. However, most data relate to mortality risk in patients with advanced CKD. There is limited evidence regarding patients with mild to moderate CKD, outcomes such as cardiovascular events, types of LTCs and regarding patients from low or middle income countries. Prospero Registration: CRD42019147424

Comparing the interobserver reproducibility of different regions of interest on multi-parametric renal magnetic resonance imaging in healthy volunteers, patients with heart failure and renal transplant recipients

Objective: To assess interobserver reproducibility of different regions of interest (ROIs) on multi-parametric renal MRI using commercially available software. Materials and methods: Healthy volunteers (HV), patients with heart failure (HF) and renal transplant recipients (Tx) were recruited. Localiser scans, T1 mapping and pseudo-continuous arterial spin labelling (pCASL) were performed. HV and Tx also underwent diffusion-weighted imaging to allow calculation of apparent diffusion coefficient (ADC). For T1, pCASL and ADC, ROIs were drawn for whole kidney (WK), cortex (Cx), user-defined representative cortex (rep-Cx) and medulla. Intraclass correlation coefficient (ICC) and coefficient of variation (CoV) were assessed. Results: Forty participants were included (10 HV, 10 HF and 20 Tx). The ICC for renal volume was 0.97 and CoV 6.5%. For T1 and ADC, WK, Cx, and rep-Cx were highly reproducible with ICC ≥ 0.76 and CoV < 5%. However, cortical pCASL results were more variable (ICC > 0.86, but CoV up to 14.2%). While reproducible, WK values were derived from a wide spread of data (ROI standard deviation 17% to 55% of the mean value for ADC and pCASL, respectively). Renal volume differed between groups (p < 0.001), while mean cortical T1 values were greater in Tx compared to HV (p = 0.009) and HF (p = 0.02). Medullary T1 values were also higher in Tx than HV (p = 0.03), while medullary pCASL values were significantly lower in Tx compared to HV and HF (p = 0.03 for both). Discussion: Kidney volume calculated by manually contouring a localiser scan was highly reproducible between observers and detected significant differences across patient groups. For T1, pCASL and ADC, Cx and rep-Cx ROIs are generally reproducible with advantages over WK values

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Left ventricular dysfunction with preserved ejection fraction: the most common left ventricular disorder in chronic kidney disease patients

Chronic kidney disease (CKD) is a risk factor for premature cardiovascular disease. As kidney function declines, the presence of left ventricular abnormalities increases such that by the time kidney replacement therapy is required with dialysis or kidney transplantation, more than two-thirds of patients have left ventricular hypertrophy. Historically, much research in nephrology has focussed on the structural and functional aspects of cardiac disease in CKD, particularly using echocardiography to describe these abnormalities. There is a need to translate knowledge around these imaging findings to clinical outcomes such as unplanned hospital admission with heart failure and premature cardiovascular death. Left ventricular hypertrophy and cardiac fibrosis, which are common in CKD, predispose to the clinical syndrome of heart failure with preserved left ventricular ejection fraction (HFpEF). There is a bidirectional relationship between CKD and HFpEF, whereby CKD is a risk factor for HFpEF and CKD impacts outcomes for patients with HFpEF. There have been major improvements in outcomes for patients with heart failure and reduced left ventricular ejection fraction as a result of several large randomized controlled trials. Finding therapy for HFpEF has been more elusive, although recent data suggest that sodium-glucose cotransporter 2 inhibition offers a novel evidence-based class of therapy that improves outcomes in HFpEF. These observations have emerged as this class of drugs has also become the standard of care for many patients with proteinuric CKD, suggesting that there is now hope for addressing the combination of HFpEF and CKD in parallel. In this review we summarize the epidemiology, pathophysiology, diagnostic strategies and treatment of HFpEF with a focus on patients with CKD

Predicting outcome in acute interstitial nephritis: a case series examining the importance of histological parameters

Background: The clinical significance of common histological parameters in acute interstitial nephritis (AIN) is uncertain. We aimed to evaluate the utility of histology in predicting clinical outcomes in patients with AIN. Methods and results: Adult renal biopsies yielding a diagnosis of AIN between 2000 and 2015 were re‐examined. Patients were divided into groups based on: 1) the percentage of non‐fibrotic cortex containing inflammation (NFI‐score), (NFI‐1=0‐24%, NFI‐2=25‐74%, NFI‐3=75‐100%), and 2) the percentage of cortex containing tubular atrophy (TA score), (TA1=0‐9%, TA2=10‐24%, TA3=25‐100%). The primary outcome was a composite of ≥50% reduction in serum creatinine (sCr) or an eGFR >60 ml/min/1.73m2 1‐year post‐biopsy. From a total of 2817 native renal biopsies, there were 120 patients with AIN and adequate data for analysis. Of these, 66 (56%) achieved the primary outcome. On univariable logistic regression, NFI‐3 was associated with a 16 times increased likelihood of achieving the primary outcome compared to NFI‐1 (OR 16 (95% CI 5.2‐50)). In contrast, TA3 were associated with a 90% reduced likelihood of achieving the primary outcome compared to TA1 (OR=0.10 (95%CI 0.0‐0.3)). Maximal clinical utility was achieved by combining TA and NFI into a single prognostic ‘TANFI’ score, which had an independent predictive effect on the primary outcome in a multivariable regression model consisting of age, sex, baseline sCr and identified drug cause. Conclusions: In patients with biopsy‐proven AIN, a lower percentage of cortical tubular atrophy and, paradoxically, a higher percentage of inflammation in non‐fibrosed cortex were associated with an increased likelihood of a positive clinical outcome