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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.

Introduction:\ud \ud End stage renal disease (ESRD) is the irreversible deterioration of renal function requiring renal replacement therapy by dialysis or transplant. Human leucocyte antigens (HLA) have been well examined however research still is required into the non-HLA antibodies. Antibody mediated rejection (AMR) can be seen in the absence of HLA antibodies on biopsies of patients who have received identical transplants; anti-endothelial cell antibodies may explain this. Investigation into endothelial cell antigens on donor and recipient endothelium may elucidate and stratify the degree of risk of any given transplant and may guide towards the best matched donor.\ud \ud Methods:\ud \ud Protein array analysis was carried out on 8 patient pairs using nitro-cellulose membranes and biotinylated detection antibodies. The fluorescence emitted was captured by X-Ray film and results were recorded with ImageJ software. A fold increase of more than 2 was considered to be positive.\ud \ud Results:\ud \ud 11 proteins identified had a fold increase of increase ≥2 and were present in ≥2 patient pairs which may point to potential clinical utility. Nectin2/CD112 may be measured in order analyse graft survival time in transplant recipients. Prognosticating renal failure has clinical importance and potential markers that have been identified to aid which include MEPE, CRELD2, and TIMP-4. Novel pharmacological therapies for specific biomarkers identified in this study include JAM-A, E-Selectin, CD147, Galectin-3, JAM-C, PAR-1, and TNFR2.\ud \ud Conclusion:\ud \ud Protein analysis showed differences in expression of antigens between patients with and without Chronic Kidney Disease (CKD). This information could be used at the matching stage of renal transplantation and also in the treatment of rejection episodes. The results highlight biomarkers that potentially prognosticate and pharmacological therapies that may ameliorate kidney disease and rejection in ESRD and transplant recipients.

Background:\ud Patients with end-stage kidney disease (ESKD) are at increased risk premature death, with cardiovascular disease being the predominant mode of death. We hypothesized that left ventricular global longitudinal strain (LV-GLS) measured by feature tracking cardiovascular magnetic resonance imaging (CMR) would be associated with all-cause mortality in patients with ESKD.\ud \ud Methods:\ud A pooled analysis of CMR studies in patients with ESKD acquired within a single centre between 2002 and 2016 was carried out. CMR parameters including left ventricular ejection fraction (LVEF), LV mass index (LVMI), left atrial emptying fraction (LAEF) and LV-GLS were measured. We tested independent associations of CMR parameters with survival using a multivariable Cox model.\ud \ud Results:\ud Among 215 patients (mean age: 54 years, 62% male), mortality was 53% over 5.0 years median follow-up. The median LVEF was 64.7% (IQR 58.5, 70.0) and median LV-GLS was -15.3% (-17.24, -13.6). While 90% of patients had preserved LVEF (>50%), 58% of this group had abnormal LVGLS (>-16%). On multivariable Cox regression, age (HR: 1.04, 95%CI: 1.02-1.05), future-renal transplant (HR 0.29 95%CI: 0.17-0.47), LAEF (HR: 0.98, 95%CI: 0.96-1.00) and LV-GLS (HR: 1.08, 95%CI: 1.01-1.16) were independently associated with mortality.\ud \ud Conclusions:\ud In this cohort of patients with ESKD, LV-GLS on feature tracking CMR and LAEF were associated with all-cause mortality, independent of baseline clinical variables and future renal transplantation. This effect was present even when >90% of the cohort had normal left ventricular ejection fraction (LVEF). Using LV-GLS, instead of LVEF, to diagnose cardiac dysfunction in patients with ESKD could result in a major advance in our understanding of cardiovascular disease in ESKD.

Additional file 1. Supplementary material: S1. Baseline characteristics of participants. S2. Summary of clinically significant incidental findings. S3. Intra- and inter-observer reproducibility for cardiovascular MRI parameters. S4. Determinants of blood pool native T1. S5. Analyses exploring the potential influence of intravenous iron therapy on native T1.

BACKGROUND: Hyperphosphataemia is an independent risk factor for accelerated cardiovascular disease in chronic kidney disease (CKD), although the mechanism for this is poorly understood. We investigated the effects of sustained exposure to a high-phosphate environment on endothelial function in cellular and preclinical models, as well as in human subjects.METHODS: Resistance vessels from rats and humans (± CKD) were incubated in a normal (1.18 mM) or high (2.5 mM) phosphate concentration solution and cells were cultured in normal- (0.5 mM) or high-phosphate (3 mM) concentration media. A single-blind crossover study was performed in healthy volunteers, receiving phosphate supplements or a phosphate binder (lanthanum), and endothelial function measured was by flow-mediated dilatation.RESULTS: Endothelium-dependent vasodilatation was impaired when resistance vessels were exposed to high phosphate; this could be reversed in the presence of a phosphodiesterase-5-inhibitor. Vessels from patients with CKD relaxed normally when incubated in normal-phosphate conditions, suggesting that the detrimental effects of phosphate may be reversible. Exposure to high-phosphate disrupted the whole nitric oxide pathway with reduced nitric oxide and cyclic guanosine monophosphate production and total and phospho endothelial nitric oxide synthase expression. In humans, endothelial function was reduced by chronic phosphate loading independent of serum phosphate, but was associated with higher urinary phosphate excretion and serum fibroblast growth factor 23.CONCLUSIONS: These directly detrimental effects of phosphate, independent of other factors in the uraemic environment, may explain the increased cardiovascular risk associated with phosphate in CKD.

Patients commencing on haemodialysis (HD) have an increased risk of cardiovascular events in the first year after starting HD compared to those patients established on HD longer. Left ventricular (LV) hypertrophy and abnormal myocardial strain predict mortality. There may be changes in the myocardium of incident HD patients over a 6-month period of HD which may explain changes in cardiovascular risk. We used CMR to consider changes in LV mass, myocardial strain and T1 mapping. We examined changes in pre-dialysis highly sensitive troponin T. 33 patients undergoing HD for

Noninvasive quantification of myocardial fibrosis in end-stage renal disease is challenging. Gadolinium contrast agents previously used for cardiac magnetic resonance imaging (MRI) are contraindicated because of an association with nephrogenic systemic fibrosis. In other populations, increased myocardial native T1 times on cardiac MRI have been shown to be a surrogate marker of myocardial fibrosis. We applied this method to 33 incident hemodialysis patients and 28 age- and sex-matched healthy volunteers who underwent MRI at 3.0T. Native T1 relaxation times and feature tracking–derived global longitudinal strain as potential markers of fibrosis were compared and associated with cardiac biomarkers. Left ventricular mass indices were higher in the hemodialysis than the control group. Global, Septal and midseptal T1 times were all significantly higher in the hemodialysis group (global T1 hemodialysis 1171 ± 27 ms vs. 1154 ± 32 ms; septal T1 hemodialysis 1184 ± 29 ms vs. 1163 ± 30 ms; and midseptal T1 hemodialysis 1184 ± 34 ms vs. 1161 ± 29 ms). In the hemodialysis group, T1 times correlated with left ventricular mass indices. Septal T1 times correlated with troponin and electrocardiogram-corrected QT interval. The peak global longitudinal strain was significantly reduced in the hemodialysis group (hemodialysis -17.7±5.3% vs. -21.8±6.2%). For hemodialysis patients, the peak global longitudinal strain significantly correlated with left ventricular mass indices (R = 0.426), and a trend was seen for correlation with galectin-3, a biomarker of cardiac fibrosis. Thus, cardiac tissue properties of hemodialysis patients consistent with myocardial fibrosis can be determined noninvasively and associated with multiple structural and functional abnormalities.

Background and purpose:\ud End stage renal disease (ESRD) requiring hemodialysis (HD) carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge concerning risk factors and management strategies derived from the general population may not be applicable to those with ESRD. We studied a large ESRD population to identify risk factors and outcomes for stroke.\ud \ud Methods: \ud All adult patients receiving HD for ESRD from 01/01/2007 to 31/12/2012 were extracted from the electronic patient record. Variables associated with stroke were identified by survival analysis; demographic, clinical, imaging and dialysis related variables were assessed and case-fatality determined. Follow-up was until 31/12/2013.\ud \ud Results:\ud 1382 patients were identified (mean age 60.5 years, 58.5% male). The prevalence of AF was 21.2% and 59.4% were incident HD patients. 160 (11.6%) experienced a stroke during 3471 patient-years of follow-up (95% ischemic). Stroke incidence was 41.5/1000 patient-years in prevalent and 50.1/1000 patient-years in incident HD patients. Factors associated with stroke on regression analysis were prior stroke, diabetes and age at starting renal replacement therapy. AF was not significantly associated with stroke and warfarin did not affect stroke risk in warfarin treated patients. Fatality was 18.8% at 7, 26.9% at 28 and 56.3% 365 days after stroke.\ud \ud Conclusions:\ud Incidence of stroke is high in patients with ESRD on HD with high case-fatality. Incident HD patients had the highest stroke incidence. Many, but not all, important risk factors commonly associated with stroke in the general population were not associated with stroke in patients receiving HD.

Background:\ud Premature cardiovascular (CV) death is the commonest cause of death in renal transplant recipients. Abnormalities of left ventricular (LV) structure (collectively termed uremic cardiomyopathy) and left atrial (LA) dilation, a marker of fluid status and diastolic function, are risk factors for reduced survival in patients with end stage renal disease (ESRD). In the present analysis, we studied the impact of pre-transplant LA and LV abnormalities on survival after successful renal transplantation (RT).\ud \ud Methods:\ud One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.\ud \ud Results:\ud Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.\ud \ud Conclusions:\ud Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.\ud \ud METHODS:\ud One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.\ud \ud RESULTS:\ud Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.\ud \ud CONCLUSIONS:\ud Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.