Myocardial changes on 3T cardiovascular magnetic resonance imaging in response to haemodialysis with fluid removal.

BACKGROUND: Mapping of left ventricular (LV) native T1 is a promising non-invasive, non-contrast imaging biomarker. Native myocardial T1 times are prolonged in patients requiring dialysis, but there are concerns that the dialysis process and fluctuating fluid status may confound results in this population. We aimed to assess the changes in cardiac parameters on 3T cardiovascular magnetic resonance (CMR) before and after haemodialysis, with a specific focus on native T1 mapping. METHODS: This is a single centre, prospective observational study in which maintenance haemodialysis patients underwent CMR before and after dialysis (both scans within 24 h). Weight measurement, bio-impedance body composition monitoring, haemodialysis details and fluid intake were recorded. CMR protocol included cine imaging and mapping native T1 and T2. RESULTS: Twenty-six participants (16 male, 65 ± 9 years) were included in the analysis. The median net ultrafiltration volume on dialysis was 2.3 L (IQR 1.8, 2.5), resulting in a median weight reduction at post-dialysis scan of 1.35 kg (IQR 1.0, 1.9), with a median reduction in over-hydration (as measured by bioimpedance) of 0.75 L (IQR 0.5, 1.4). Significant reductions were observed in LV end-diastolic volume (- 25 ml, p = 0.002), LV stroke volume (- 13 ml, p = 0.007), global T1 (21 ms, p = 0.02), global T2 (- 1.2 ms, p = 0.02) following dialysis. There was no change in LV mass (p = 0.35), LV ejection fraction (p = 0.13) or global longitudinal strain (p = 0.22). On linear regression there was no association between baseline over-hydration (as defined by bioimpedance) and global native T1 or global T2, nor was there an association between the change in over-hydration and the change in these parameters. CONCLUSIONS: Acute changes in cardiac volumes and myocardial native T1 are detectable on 3T CMR following haemodialysis with fluid removal. The reduction in global T1 suggests that the abnormal native T1 observed in patients on haemodialysis is not entirely due to myocardial fibrosis.

Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study.

BACKGROUND: The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months. METHODS: ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation. Changes in left ventricular ejection fraction (LVEF), left ventricular mass (LVM), left atrial diameter (LAD), aortic root diameter (AoRD), E:A, and E deceleration time (EDT) were compared between study arms. Analyses were performed using t-tests and multivariate linear regression. RESULTS: Ninety two patients were included (50 medical versus 42 revascularization). There was no difference between arms in any baseline echocardiographic parameter. Comparisons of longitudinal changes in echocardiographic measurements were: δLVEF medical 0.8 ± 8.7% versus revascularization - 2.8 ± 6.8% (p = 0.05), δLVM - 2.9 ± 33 versus - 1.7 ± 39 g (p = 0.9), δLAD 0.1 ± 0.4 versus 0.01 ± 0.5 cm (p = 0.3), δAoRD 0.002 ± 0.3 versus 0.06 ± 0.3 cm (p = 0.4), δE:A - 0.0005 ± 0.6 versus 0.03 ± 0.7 (p = 0.8), δEDT - 1.1 ± 55.5 versus - 9.0 ± 70.2 ms (p = 0.6). In multivariate models, there were no differences between treatment groups for any parameter at 12 months. Likewise, change in blood pressure did not differ between arms (mean δsystolic blood pressure medical 0 mmHg [range - 56 to + 54], revascularization - 3 mmHg [- 61 to + 59], p = 0.60). CONCLUSIONS: This sub-study did not show any significant differences in cardiac structure and function accompanying renal revascularization in ASTRAL. Limitations include the small sample size, the relative insensitivity of echocardiography, and the fact that a large proportion of ASTRAL patient population had only modest renal artery stenosis as described in the main study.

Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway.

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.

Research cardiac magnetic resonance imaging in end stage renal disease - incidence, significance and implications of unexpected incidental findings.

OBJECTIVES: Left ventricular mass (LVM) at cardiac magnetic resonance imaging (CMR) is a frequent end point in clinical trials in nephrology. Trial participants with end stage renal disease (ESRD) may have a greater frequency of incidental findings (IF). We retrospectively investigated prevalence of IF in previous research CMR and reviewed their subsequent impact on participants. METHODS: Between 2002 and 2006, 161 ESRD patients underwent CMR in a transplant assessment study. Images were used to assess LV mass and function. In the current study a radiologist reviewed the scans for IF. Review of patient records determined the subsequent clinical significance of IF. RESULTS: There were 150 IF in 95 study participants. Eighty-four (56 %) were new diagnoses. One hundred and two were non-cardiac. Fifteen were suspicious of malignancy. There was a clinically significant IF for 14.9 % of the participants. In six cases earlier identification of an IF may have improved quality of life or survival. CONCLUSIONS: Without radiology support clinically important IF may be missed on CMR. Patients undergoing CMR in trials should be counselled about the frequency and implications of IF. Patients with ESRD have a higher prevalence of IF than reported in other populations. Nephrology studies require mechanisms for radiologist reporting and strategies for dealing with IF. KEY POINTS: • Incidental findings on research cardiac magnetic resonance imaging can have significant consequences. • We considered incidental findings in historical renal cardiac resonance imaging clinical trials. • Incidental findings are common and important in the chronic kidney disease population. • Without radiology support, clinically significant incidental findings may be missed on imaging. • Study protocols, approvals and consent processes should take account of possible findings.

Renal association clinical practice guideline in post-operative care in the kidney transplant recipient.

These guidelines cover the care of patients from the period following kidney transplantation until the transplant is no longer working or the patient dies. During the early phase prevention of acute rejection and infection are the priority. After around 3-6 months, the priorities change to preservation of transplant function and avoiding the long-term complications of immunosuppressive medication (the medication used to suppress the immune system to prevent rejection). The topics discussed include organization of outpatient follow up, immunosuppressive medication, treatment of acute and chronic rejection, and prevention of complications. The potential complications discussed include heart disease, infection, cancer, bone disease and blood disorders. There is also a section on contraception and reproductive issues.Immediately after the introduction there is a statement of all the recommendations. These recommendations are written in a language that we think should be understandable by many patients, relatives, carers and other interested people. Consequently we have not reworded or restated them in this lay summary. They are graded 1 or 2 depending on the strength of the recommendation by the authors, and AD depending on the quality of the evidence that the recommendation is based on.

Blood transcriptional signature of recombinant human erythropoietin administration and implications for antidoping strategies.

Recombinant human erythropoietin (rHuEPO) is frequently abused by athletes as a performance-enhancing drug, despite being prohibited by the World Anti-Doping Agency. Although the methods to detect blood doping, including rHuEPO injections, have improved in recent years, they remain imperfect. In a proof-of-principle study, we identified, replicated, and validated the whole blood transcriptional signature of rHuEPO in endurance-trained Caucasian males at sea level (n = 18) and Kenyan endurance runners at moderate altitude (n = 20), all of whom received rHuEPO injections for 4 wk. Transcriptional profiling shows that hundreds of transcripts were altered by rHuEPO in both cohorts. The main regulated expression pattern, observed in all participants, was characterized by a "rebound" effect with a profound upregulation during rHuEPO and a subsequent downregulation up to 4 wk postadministration. The functions of the identified genes were mainly related to the functional and structural properties of the red blood cell. Of the genes identified to be differentially expressed during and post-rHuEPO, we further confirmed a whole blood 34-transcript signature that can distinguish between samples collected pre-, during, and post-rHuEPO administration. By providing biomarkers that can reveal rHuEPO use, our findings represent an advance in the development of new methods for the detection of blood doping.

Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping.

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.

Phosphate as a cardiovascular risk factor: effects on vascular and endothelial function.

BACKGROUND: Hyperphosphataemia is a risk factor for accelerated cardiovascular disease in chronic kidney disease. The mechanism is poorly understood; it is unclear whether phosphate has direct effects or effects mediated via calcification or FGF23. We investigated direct effects of phosphate on endothelial function using myography to study rat and human blood vessels. In addition we assessed the effects of phosphate loading on endothelial function in a clinical study. METHODS: Resistance vessels from patients with (n=12) and without (n=13) chronic kidney disease were incubated in normal or high phosphate. Vasoconstrictor and vasorelaxation responses were measured. Concentration-response curves were constructed and comparisons made. Identical experiments were performed in rat mesenteric vessels with and without phosphodiesterase type 5 inhibitor. A cross-over study was done in 19 healthy volunteers receiving phosphate supplements or binders and endothelial function measured by flow mediated dilatation (FMD). Primary outcome was percent change in FMD from baseline. FINDINGS: Nine to 13 vessels were used in each group. Endothelium-dependent vasodilatation was impaired in high compared with normal phosphate in rat (mean maximum vasodilatation 64% [SE 9] vs 95 [1], p<0·001) and human vessels with (25·3 [11·1] vs 75·7 [13·6], p<0·001) and without chronic kidney disease (42·9 [12] vs 79·4 [8·2], p=0·003). In rat vessels, these effects were reversed by a phosphodiesterase type 5 inhibitor. In vivo in volunteers, endothelial function was reduced by phosphate loading (median maximum vasodilatation 3·38% [IQR 2·57-5·26] vs 8·4 [6·2-11·6], p<0·001); this effect was independent of serum phosphate concentration but associated with urinary phosphate excretion and serum FGF23 concentrations. INTERPRETATION: Prolonged exposure to phosphate is associated with endothelial dysfunction, a direct effect of phosphate, which might contribute to cardiovascular risk in chronic kidney disease. In a high phosphate environment, endothelial and vascular dysfunction is evident in blood vessels and in man exposed to prolonged oral phosphate loading. These effects might be mediated by disruption of the NO pathway. FUNDING: British Heart Foundation, Darlinda's Charity for Renal Research.

Risk factors and outcome of stroke in renal transplant recipients.

Stroke incidence is high in end-stage renal disease, and risk factors differ between the dialysis and general populations. However, risk factors and outcomes following renal transplantation remain unclear. We analyzed all adult patients with a functioning renal transplant from 01/01/2007 to 12/31/2012. Data were extracted from the electronic patient record. Variables associated with stroke were identified by survival analyses; demographic, clinical, and imaging and laboratory variables were assessed and case fatality determined. Follow-up was until 05/12/2013. A total of 956 patients were identified (median age 40.1 years, 59.9% male). Atrial fibrillation (AF) prevalence was 9.2%, and 38.2% received a transplant during follow-up. A total of 26 (2.7%) experienced a stroke during 4409 patient-years of follow-up (84.6% ischemic). Stroke incidence was 5.96/1000 patient-years. Factors associated with stroke on regression analysis were prior stroke, diabetes, age, systolic hypertension, and hemoglobin. Atrial fibrillation was associated with time to stroke (P<0.001). Warfarin did not associate with ischemic stroke risk in those with AF. Fatality was 19.2% at 7, 23.1% at 28, and 42.3% at 365 days after stroke. Patients with a functioning renal transplant have a high stroke incidence and case fatality. Unlike those on hemodialysis, risk factors are similar to the general population. We did not demonstrate benefit from warfarin use in those with AF.

Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis.

BACKGROUND AND PURPOSE: End-stage renal disease (ESRD) requiring hemodialysis carries up to a 10-fold greater risk of stroke than normal renal function. Knowledge on 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. METHODS: All adult patients receiving hemodialysis for ESRD from January 1, 2007, to December 31, 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 was determined. Follow-up was until December 31, 2013. RESULTS: A total of 1382 patients were identified (mean age, 60.5 years; 58.5% men). The prevalence of atrial fibrillation was 21.2%, and 59.4% were incident hemodialysis patients. One hundred and sixty patients (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 hemodialysis patients. Factors associated with stroke on regression analysis were prior stroke, diabetes mellitus, and age at starting renal replacement therapy. Atrial fibrillation was not significantly associated with stroke, and warfarin did not affect stroke risk in warfarin-treated patients. Fatality was 18.8% at 7 days, 26.9% at 28 days, and 56.3% at 365 days after stroke. CONCLUSIONS: Incidence of stroke is high in patients with ESRD on hemodialysis with high case-fatality. Incident hemodialysis 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 hemodialysis.

Teaching percutaneous renal biopsy using unfixed human cadavers.

BACKGROUND: Percutaneous renal biopsy (PRB) is an important diagnostic procedure. Despite advances in its safety profile there remains a small but significant risk of bleeding complications. Traditionally, operators train to perform PRB through tutor instruction and directly supervised PRB attempts on real patients. We describe an approach to teaching operators to perform PRB using cadaveric simulation. METHODS: We devised a full day course hosted in the Clinical Anatomy Skills Centre, with places for nine candidates. Course faculty consisted of two Consultant Nephrologists, two Nephrology trainees experienced in PRB, and one Radiologist. Classroom instruction included discussion of PRB indications, risk minimisation, and management of complications. Two faculty members acted as models for the demonstration of kidney localisation using real-time ultrasound scanning. PRB was demonstrated using a cadaveric model, and candidates then practised PRB using each cadaver model. RESULTS: Written candidate feedback was universally positive. Faculty considered the cadaveric model a realistic representation of live patients, while the use of multiple cadavers introduced anatomical variation. CONCLUSIONS: Our model facilitates safe simulation of a high risk procedure. This might reduce serious harm associated with PRB and improve patient safety, benefiting trainee operators and patients alike.

Serum phosphate and social deprivation independently predict all-cause mortality in chronic kidney disease.

BACKGROUND: Hyperphosphataemia is linked to cardiovascular disease and mortality in chronic kidney disease (CKD). Outcome in CKD is also affected by socioeconomic status. The objective of this study was to assess the associations between serum phosphate, multiple deprivation and outcome in CKD patients. METHODS: All adult patients currently not on renal replacement therapy (RRT), with first time attendance to the renal outpatient clinics in the Glasgow area between July 2010 and June 2014, were included in this prospective study. Area socioeconomic status was assessed as quintiles of the Scottish Index of Multiple Deprivation (SIMD). Outcomes were all-cause and cardiovascular mortality and commencement of RRT. RESULTS: The cohort included 2950 patients with a median (interquartile range) age 67.6 (53.6-76.9) years. Median (interquartile range) eGFR was 38.1 (26.3-63.5) ml/min/1.73 m(2), mean (± standard deviation) phosphate was 1.13 (± 0.24) mmol/L and 31.6 % belonged to the most deprived quintile (SIMD quintile I). During follow-up 375 patients died and 98 commenced RRT. Phosphate ≥ 1.50 mmol/L was associated with all-cause (hazard ratio (HR) 2.51; 95 % confidence interval (CI) 1.63-3.89) and cardiovascular (HR 5.05; 95 % CI 1.90-13.46) mortality when compared to phosphate 0.90-1.09 mmol/L in multivariable analyses. SIMD quintile I was independently associated with all-cause mortality. Phosphate did not weaken the association between deprivation index and mortality, and there was no interaction between phosphate and SIMD quintiles. Neither phosphate nor SIMD predicted commencement of RRT. CONCLUSIONS: Multiple deprivation and serum phosphate were strong, independent predictors of all-cause mortality in CKD and showed no interaction. Phosphate also predicted cardiovascular mortality. The results suggest that phosphate lowering should be pursued regardless of socioeconomic status.

Inter-study reproducibility of arterial spin labelling magnetic resonance imaging for measurement of renal perfusion in healthy volunteers at 3 Tesla.

BACKGROUND: Measurement of renal perfusion is a crucial part of measuring kidney function. Arterial spin labelling magnetic resonance imaging (ASL MRI) is a non-invasive method of measuring renal perfusion using magnetised blood as endogenous contrast. We studied the reproducibility of ASL MRI in normal volunteers. METHODS: ASL MRI was performed in healthy volunteers on 2 occasions using a 3.0 Tesla MRI scanner with flow-sensitive alternating inversion recovery (FAIR) perfusion preparation with a steady state free precession (True-FISP) pulse sequence. Kidney volume was measured from the scanned images. Routine serum and urine biochemistry were measured prior to MRI scanning. RESULTS: 12 volunteers were recruited yielding 24 kidneys, with a mean participant age of 44.1 ± 14.6 years, blood pressure of 136/82 mmHg and chronic kidney disease epidemiology formula estimated glomerular filtration rate (CKD EPI eGFR) of 98.3 ± 15.1 ml/min/1.73 m2. Mean kidney volumes measured using the ellipsoid formula and voxel count method were 123.5 ± 25.5 cm3, and 156.7 ± 28.9 cm3 respectively. Mean kidney perfusion was 229 ± 41 ml/min/100 g and mean cortical perfusion was 327 ± 63 ml/min/100 g, with no significant differences between ASL MRIs. Mean absolute kidney perfusion calculated from kidney volume measured during the scan was 373 ± 71 ml/min. Bland Altman plots were constructed of the cortical and whole kidney perfusion measurements made at ASL MRIs 1 and 2. These showed good agreement between measurements, with a random distribution of means plotted against differences observed. The intra class correlation for cortical perfusion was 0.85, whilst the within subject coefficient of variance was 9.2%. The intra class correlation for whole kidney perfusion was 0.86, whilst the within subject coefficient of variance was 7.1%. CONCLUSIONS: ASL MRI at 3.0 Tesla provides a repeatable method of measuring renal perfusion in healthy subjects without the need for administration of exogenous compounds. We have established normal values for renal perfusion using ASL MRI in a cohort of healthy volunteers.

Measuring congestion with a non-invasive monitoring device in heart failure and haemodialysis: CONGEST-HF.

AIMS: We examined the effectiveness of a novel cardiopulmonary management wearable sensor (worn for less than 5 mins) at measuring congestion and correlated the device findings with established clinical measures of congestion. METHODS AND RESULTS: We enrolled three cohorts of patients: (1) patients with heart failure (HF) receiving intravenous diuretics in hospital; (2) patients established on haemodialysis, and (3) HF patients undergoing right heart catheterization (RHC). The primary outcomes in the respective cohorts were a Spearman correlation between (1) change in weight and change in thoracic impedance (TI) (from enrolment, 24 h after admission to discharge) in patients hospitalized for HF; (2) lung ultrasound B-lines and volume removed during dialysis with device measured TI, and (3) pulmonary capillary wedge pressure (PCWP) and sub-acoustic diastolic, third heart sound (S3) in the patients undergoing RHC. A total of 66 patients were enrolled. In HF patients (n = 25), change in weight was correlated with both change in device TI (Spearman correlation [rsp] = -0.64, p = 0.002) and change in device S3 (rsp = -0.53, p = 0.014). In the haemodialysis cohort (n = 21), B-lines and TI were strongly correlated before (rsp = -0.71, p < 0.001) and after (rsp = -0.77, p < 0.001) dialysis. Volume of fluid removed by dialysis was correlated with change in device TI (rsp = 0.49, p = 0.024). In the RHC cohort (n = 20), PCWP measured at one time point and device S3 were not significantly correlated (rsp = 0.230, p = 0.204). There were no device-related adverse events. CONCLUSIONS: A non-invasive device was able to detect changes in congestion in patients with HF receiving decongestion therapy and patients having fluid removed at haemodialysis. The cardiopulmonary management device, which measures multiple parameters, is a potentially useful tool to monitor patients with HF to prevent hospitalizations.

Urinary corticosteroid excretion predicts left ventricular mass and proteinuria in chronic kidney disease.

Blockade of the MR (mineralocorticoid receptor) in CKD (chronic kidney disease) reduces LVMI [LV (left ventricular) mass index] and proteinuria. The MR can be activated by aldosterone, cortisol and DOC (deoxycorticosterone). The aim of the present study was to explore the influence of mineralocorticoids on LVMI and proteinuria in patients with CKD. A total of 70 patients with CKD and 30 patients with EH (essential hypertension) were recruited. Patients underwent clinical phenotyping; biochemical assessment and 24 h urinary collection for THAldo (tetrahydroaldosterone), THDOC (tetrahydrodeoxycorticosterone), cortisol metabolites (measured using GC-MS), and urinary electrolytes and protein [QP (proteinuira quantification)]. LVMI was measured using CMRI (cardiac magnetic resonance imaging). Factors that correlated significantly with LVMI and proteinuria were entered into linear regression models. In patients with CKD, significant predictors of LVMI were male gender, SBP (systolic blood pressure), QP, and THAldo and THDOC excretion. Significant independent predictors on multivariate analysis were THDOC excretion, SBP and male gender. In EH, no association was seen between THAldo or THDOC and LVMI; plasma aldosterone concentration was the only significant independent predictor. Significant univariate determinants of proteinuria in patients with CKD were THAldo, THDOC, USod (urinary sodium) and SBP. Only THAldo excretion and SBP were significant multivariate determinants. Using CMRI to determine LVMI we have demonstrated that THDOC is a novel independent predictor of LVMI in patients with CKD, differing from patients with EH. Twenty-four hour THAldo excretion is an independent determinant of proteinuria in patients with CKD. These findings emphasize the importance of MR activation in the pathogenesis of the adverse clinical phenotype in CKD.

Altered relative concentrations of high-energy phosphates in patients with uraemic cardiomyopathy measured by magnetic resonance spectroscopy.

BACKGROUND: Premature sudden cardiovascular death is the commonest cause of death in end-stage renal disease (ESRD) patients and is associated with uraemic cardiomyopathy [left ventricular hypertrophy (LVH), systolic dysfunction (LVSD) or LV dilation]. High-energy phosphates (HEP), quantified using phosphorus-31 magnetic resonance spectroscopy, are reduced in patients with diabetes, heart failure and uraemia. Phosphocreatine:ß adenosine triphosphate (PCr:ATP) ratio is an index of metabolic activity. We compared resting HEPs in ESRD patients and hypertensive patients (with and without LVH) who had normal renal function (LVH-only or normal myocardia). We also assessed associations of HEP levels with abnormalities of uraemic cardiomyopathy. METHODS: Fifty-three ESRD and 30 hypertensive patients (18 with LVH, 12 with normal myocardia) underwent phosphorus magnetic resonance spectroscopy of their left ventricle. PCr:ATP ratios were calculated from (31)P-MR spectra obtained from long-axis views of the left ventricle. RESULTS: There were no significant differences in age, LV mass, chamber sizes and ejection fraction between patient groups. PCr:ATP was significantly lower in ESRD patients compared to hypertensive patients, irrespective of the presence or absence of LVH (P = 0.01). In the ESRD group, PCr:ATP was significantly lower in patients with LVSD (P = 0.05) and LV dilation (P = 0.01). LVH was not associated with significant difference in PCr:ATP. CONCLUSIONS: ESRD patients have lower HEP levels compared to hypertensive patients. Lower PCr:ATP ratio, indicating altered myocardial metabolic function in ESRD patients, is associated with features of uraemic cardiomyopathy.

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.

Association between proteinuria and left ventricular mass index: a cardiac MRI study in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. We hypothesized that the level of proteinuria would correlate with left ventricular mass, providing a potential link between elevated protein excretion, left ventricular hypertrophy (LVH) and the increased mortality seen in patients with CKD. In order to do this, we assessed the determinants of left ventricular mass, measured using cardiac magnetic resonance (CMR) imaging, in patients with CKD. METHODS: Patients attending the renal clinic with CKD stages 2-4 and diabetic nephropathy (n = 26) and IgA nephropathy (n = 23) were recruited. They underwent detailed demographic, biochemical and vascular phenotyping and CMR imaging. Proteinuria was measured using spot protein:creatinine ratio (PCR). Left ventricular mass index (LVMI) was calculated from short-axis cine imaging using Argus software and adjusted for body surface area. RESULTS: Log-PCR correlated significantly with LVMI, as did waist circumference, pulse pressure and systolic blood pressure. LVMI was higher in men. When these variables were entered into a linear regression model, log-PCR (P = 0.006) and systolic blood pressure (P < 0.001) independently predicted LVMI. Renal function was not associated with LVMI. CONCLUSIONS: Using volume-independent CMR imaging, we have demonstrated that the level of urinary protein excretion is independently and significantly associated with left ventricular mass in patients with CKD. This relationship was independent of blood pressure. This finding provides a novel link between CKD and increased cardiovascular risk.

A descriptive analysis of non-human leukocyte antigens present in renal transplant donor-recipient pairs.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.