Mohamed Tarek Eldehni

Circulating Endotoxemia: A Novel Factor in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Translocated endotoxin derived from intestinal bacteria has a wide range of adverse effects on cardiovascular (CV) structure and function, driving systemic inflammation, atherosclerosis and oxidative stress. This studys aim was to investigate endotoxemia across the spectrum of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Circulating endotoxin was measured in 249 patients comprising CKD stage 3 to 5 and a comparator cohort of hypertensive patients without significant renal impairment. Patients underwent extended CV assessment, including pulse wave velocity and vascular calcification. Hemodialysis (HD) patients also received detailed echocardiographic-based intradialytic assessments. Patients were followed up for 1 year to assess survival. RESULTS Circulating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality. CONCLUSIONS CKD patients are characteristically exposed to significant endotoxemia. In particular, HD-induced systemic circulatory stress and recurrent regional ischemia may lead to increased endotoxin translocation from the gut. Resultant endotoxemia is associated with systemic inflammation, markers of malnutrition, cardiac injury, and reduced survival. This represents a crucial missing link in understanding the pathophysiology of the grossly elevated CV disease risk in CKD patients, highlighting the potential toxicity of conventional HD and providing a novel set of potential therapeutic strategies to reduce CV mortality in CKD patients.

Randomized Clinical Trial of Dialysate Cooling and Effects on Brain White Matter

Hemodialysis is associated with significant circulatory stress that could produce recurrent and cumulative ischemic insults to multiple organs, such as the brain. We aimed to characterize hemodialysis-induced brain injury by longitudinally studying the effects of hemodialysis on brain white matter microstructure and further examine if the use of cooled dialysate could provide protection against hemodialysis-associated brain injury. In total, 73 patients on incident hemodialysis starting within 6 months were randomized to dialyze with a dialysate temperature of either 37°C or 0.5°C below the core body temperature and followed up for 1 year. Brain white matter microstructure was studied by diffusion tensor magnetic resonance imaging at baseline and follow-up (38 patients available for paired analysis). Intradialytic hemodynamic stress was quantified using the extrema points analysis model. Patients on hemodialysis exhibited a pattern of ischemic brain injury (increased fractional anisotropy and reduced radial diffusivity). Cooled dialysate improved hemodynamic tolerability, and changes in brain white matter were associated with hemodynamic instability (higher mean arterial pressure extrema points frequencies were associated with higher fractional anisotropy [peak r=0.443, P<0.03] and lower radial diffusivity [peak r=-0.439, P<0.02]). Patients who dialyzed at 0.5°C below core body temperature exhibited complete protection against white matter changes at 1 year. Our data suggest that hemodialysis results in significant brain injury and that improvement in hemodynamic tolerability achieved by using cooled dialysate is effective at abrogating these effects. This intervention can be delivered without additional cost and is universally applicable.

Effects of arteriovenous fistula formation on arterial stiffness and cardiovascular performance and function

BACKGROUND Native arteriovenous fistula (AVF) is the vascular access of choice and its use cf. catheters is associated with sustained reduction in mortality. This may be due to factors beyond dialysis catheter-associated sepsis. This study aimed to investigate the impact of AVF formation on the spectrum of cardiovascular factors that might be important in the pathophysiology of cardiovascular diseases in chronic kidney disease (CKD) patients. METHODS We recruited 43 pre-dialysis patients who underwent AVF formation. Patients were studied 2 weeks prior to AVF operation and 2 weeks and 3 months post-operatively. Haemodynamic variables were measured using pulse wave analysis, carotid femoral pulse wave velocity (CF-PWV) by applanation tonometry and AVF blood flow by Doppler ultrasound. Bioimpedence analysis was performed and patients underwent serial transthoracic echocardiography. RESULTS AVF formation was successful in 30/43 patients. Two weeks post-operatively, total peripheral resistance decreased (-17 ± 18%, P = 0.001), stroke volume tended to rise (12 ± 30 mL, P = 0.053) and both heart rate (4 ± 8 bpm, P = 0.01) and cardiac output (1.1 ± 1.5 L/min, P = 0.001) increased. Systolic and diastolic blood pressures (BPs) reduced (-9 ± 18 mmHg; -9 ± 10 mmHg; ≤ P = 0.006) and CF-PWV reduced (-1.1 ± 1.5 m/s, P = 0.004). Left ventricular ejection fraction (LVEF) increased (6 ± 8%, P < 0.001). All the observed changes were largely maintained after 3 months. No change in hydration status/body composition was observed. CONCLUSIONS AVF formation resulted in a sustained reduction in arterial stiffness and BP as well as an increase in LVEF. Overall, post-AVF adaptations might be characterized as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals.

Randomized Controlled Trial of Individualized Dialysate Cooling for Cardiac Protection in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Cardiovascular disease is the most common cause of death in patients on hemodialysis (HD). HD-associated cardiomyopathy is appreciated to be driven by exposure to recurrent and cumulative ischemic insults resulting from hemodynamic instability of conventionally performed intermittent HD treatment itself. Cooled dialysate reduces HD-induced recurrent ischemic injury, but whether this confers long-term protection of the heart in terms of cardiac structure and function is not known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between September 2009 and January 2013, 73 incident HD patients were randomly assigned to a dialysate temperature of 37°C (control) or individualized cooling at 0.5°C below body temperature (intervention) for 12 months. Cardiac structure, function, and aortic distensibility were assessed by cardiac magnetic resonance imaging. Mean between-group difference in delivered dialysate temperature was 1.2°C±0.3°C. Treatment effects were determined by the interaction of treatment group with time in linear mixed models. RESULTS There was no between-group difference in the primary outcome of left ventricular ejection fraction (1.5%; 95% confidence interval, -4.3% to 7.3%). However, left ventricular function assessed by peak systolic strain was preserved by the intervention (-3.3%; 95% confidence interval, -6.5% to -0.2%) as was diastolic function (measured as peak diastolic strain rate, 0.18 s(-1); 95% confidence interval, 0.02 to 0.34 s(-1)). Reduction of left ventricular dilation was demonstrated by significant reduction in left ventricular end-diastolic volume (-23.8 ml; 95% confidence interval, -44.7 to -2.9 ml). The intervention was associated with reduced left ventricular mass (-15.6 g; 95% confidence interval, -29.4 to -1.9 g). Aortic distensibility was preserved in the intervention group (1.8 mmHg(-1)×10(-3); 95% confidence interval, 0.1 to 3.6 mmHg(-1)×10(-3)). There were no intervention-related withdrawals or adverse events. CONCLUSIONS In patients new to HD, individualized cooled dialysate did not alter the primary outcome but was well tolerated and slowed the progression of HD-associated cardiomyopathy. Because cooler dialysate is universally applicable at no cost, the intervention warrants wider adoption or confirmation of these findings in a larger trial.

Troponin T for the Detection of Dialysis-Induced Myocardial Stunning in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Circulating troponin T levels are frequently elevated in patients undergoing long-term dialysis. The pathophysiology underlying these elevations is controversial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In 70 prevalent hemodialysis (HD) patients, HD-induced myocardial stunning was assessed echocardiographically at baseline and after 12 months. Nineteen patients were not available for the follow-up analysis. The extent to which predialysis troponin T was associated with the occurrence of HD-induced myocardial stunning was assessed as the primary endpoint. RESULTS The median troponin T level in this hemodialysis cohort was 0.06 ng/ml (interquartile range, 0.02-0.10). At baseline, 64% of patients experienced myocardial stunning. These patients showed significantly higher troponin T levels than patients without stunning (0.08 ng/ml [0.05-0.12] versus 0.02 ng/ml [0.01-0.05]). Troponin T levels were significantly correlated to measures of myocardial stunning severity (number of affected segments: r=0.42; change in ejection fraction from beginning of dialysis to end of dialysis: r=-0.45). In receiver-operating characteristic analyses, predialytic troponin T achieved an area under the curve of 0.82 for the detection of myocardial stunning. In multivariable analysis, only ultrafiltration volume (odds ratio, 4.38 for every additional liter) and troponin T (odds ratio, 9.33 for every additional 0.1 ng/ml) were independently associated with myocardial stunning. After 12 months, nine patients had newly developed myocardial stunning and showed a significant increase in troponin T over baseline (0.03 ng/ml at baseline versus 0.05 ng/ml at year 1). CONCLUSIONS Troponin T levels in HD patients are associated with the presence and severity of HD-induced myocardial stunning.

Cardiac assessment in chronic kidney disease

Patients with chronic kidney disease are well recognized to develop a wide range of cardiac structural and functional abnormalities. These changes may be progressive and relate directly to a grossly aggravated risk of cardiovascular events and reduced survival. Although conventional methods of cardiac assessment have been shown to be useful, they are limited by insufficient sensitivity and specificity, to fully appreciate the overall degree of myocardial distress that is common in these patients. This article aims to review the use of established and emerging cardiac imaging tools and, in particular, their application in patients with chronic kidney disease.

Rationale and design of a multi-centre randomised controlled trial of individualised cooled dialysate to prevent left ventricular systolic dysfunction in haemodialysis patients

BackgroundThe main hypothesis of this study is that patients having regular conventional haemodialysis (HD) will have a smaller decline in cardiac systolic function by using cooler dialysate. Cooler dialysate may also be beneficial for brain function.Methods/DesignThe trial is a multicentre, prospective, randomised, un-blinded, controlled trial. Patients will be randomised 1:1 to use a dialysate temperature of 37°C for 12 months or an individualised cooled dialysate. The latter will be set at 0.5°C less than the patient’s own temperature, determined from the mean of 6 prior treatment sessions with a tympanic thermometer, up to a maximum of 36°C. Protocol adherence will be regularly checked. Inclusion criteria are incident adult HD patients within 180 days of commencing in-centre treatment 3 times per week with capacity to consent for the trial and without contra-indications for magnetic resonance imaging. Exclusion criteria include not meeting inclusion criteria, inability to tolerate magnetic resonance imaging and New York Heart Association Grade IV heart failure. During the study period, resting cardiac and cerebral magnetic resonance imaging will be performed at baseline and 12 months on an inter-dialytic day. Cardiovascular performance during HD will also be assessed by continuous cardiac output monitors, intra-dialytic echocardiography and biomarkers at baseline and 12 months. The primary outcome measure is a 5% between-group difference in left ventricular ejection fraction measured by cardiac magnetic resonance imaging at 12 months compared to baseline. Analysis will be by intention-to-treat. Secondary outcome measures will include changes in cerebral microstructure and changes in cardiovascular performance during HD. A total of 73 patients have been recruited into the trial from four UK centres. The trial is funded by a Research for Patient Benefit Grant from the National Institute of Healthcare Research. AO is funded by a British Heart Foundation Clinical Research Training Fellowship Grant. The funders had no role in the design of the study.DiscussionThis investigator-initiated study has been designed to provide evidence to help nephrologists determine the optimal dialysate temperature for preserving cardiac and cerebral function in HD patients.Trial registrationISRCTN00206012 and UKCRN ID 7422

The Reimbursement and Cost of Acute Kidney Injury: A UK Hospital Perspective

Background: Despite the great interest in acute kidney injury (AKI), there have been very few studies that examined the economic impact and costing methodologies of AKI. We aimed to examine the cost and income of AKI in hospitalised patients over a period of 1 year using the NHS costing system related to that year. Methods: A total of 627 patients discharged between January 2008 and December 2008 with AKI were identified by International Classification of Disease 10 codes (ICD-10). Basic demographic data were collected using the hospital electronic records, and the severity of AKI was classified according to the Acute Kidney Injury Network (AKIN) classification. We calculated the total income and isolated the AKI income related to AKI-specific finished consultant episodes. Then we conducted a patient level costing exercise using relative value units (RVU) to compare the cost of AKI to the actual income. Results: The total spell income for all patients was GBP 1,954,922.7; the mean total income per patient was GBP 3,752.3 (95% CI 3,594.6-3,903.9). AKIN stage 3 generated significantly higher total spell and AKI income. The estimated overall cost of treating AKI was higher than the AKI income to the Primary Care Trust (GBP 1,984,543.9 vs. 1,755,395). Conclusion: AKIN stage 3 has a significant economic impact when compared with AKIN stages 1 and 2. The move towards a patient level costing using RVU could be a more efficient way to match cost and income.

Characterisation of cardiomyopathy by cardiac and aortic magnetic resonance in patients new to hemodialysis

ObjectivesCardiomyopathy is a key factor in accelerated cardiovascular mortality in haemodialysis (HD) patients. We aimed to phenotype cardiac and vascular dysfunction by tagged cardiovascular magnetic resonance (CMR) imaging in patients recently commencing HD.MethodsFifty-four HD patients and 29 age and sex-matched controls without kidney disease were studied. Left ventricular (LV) mass, volumes, ejection fraction (EF), concentric remodelling, peak-systolic circumferential strain (PSS), peak diastolic strain rate (PDSR), LV dyssynchrony, aortic distensibility and aortic pulse wave velocity were determined.ResultsGlobal systolic function was reduced (EF 51 ± 10%, HD versus 59 ± 5%, controls, p < 0.001; PSS 15.9 ± 3.7% versus 19.5 ± 3.3%, p < 0.001). Diastolic function was decreased (PDSR 1.07 ± 0.33s-1 versus 1.31 ± 0.38s-1, p = 0.003). LV mass index was increased (63[54,79]g/m2 versus 46[42,53]g/m2, p < 0.001). Anteroseptal reductions in PSS were apparent. These abnormalities remained prevalent in the subset of HD patients with preserved EF >50% (n = 35) and the subset of HD patients without diabetes (n = 40). LV dyssynchrony was inversely correlated to diastolic function, EF and aortic distensibility. Diastolic function was inversely correlated to LV dyssynchrony, concentric remodelling, age and aortic pulse wave velocity.ConclusionPatients new to HD have multiple cardiac and aortic abnormalities as characterised by tagged CMR. Cardio-protective interventions are required from initiation of therapy.Key Points• First characterisation of cardiomyopathy by tagged CMR in haemodialysis patients.• Diastolic function was correlated to LV dyssynchrony, concentric remodelling and aortic PWV.• Reductions in strain localised to the septal and anterior wall.• Bioimpedance measures were unrelated to LV strain, suggesting volume-independent pathogenetic mechanisms.• Multiple abnormalities persisted in the HD patient subset with preserved EF or without diabetes.

N-Terminal Pro-B-type Natriuretic Peptide and Its Correlation to Haemodialysis-Induced Myocardial Stunning

Background: Haemodialysis (HD) is able to induce recurrent myocardial ischemia and segmental left-ventricular dysfunction (myocardial stunning). The association of N-terminal Pro-B-type natriuretic peptide (NTpro-BNP) with HD-induced myocardial stunning is unclear. Methods: In 70 prevalent HD patients, HD-induced myocardial stunning was assessed echocardiographically at baseline and after 12 months. The extent to which pre-dialysis NTpro-BNP was associated with the occurrence of HD-induced myocardial stunning was assessed as the primary endpoint. Results: The median Ntpro-BNP concentration in this cohort was 2,154 pg/ml (IQR 1,224-3,014). Patients experiencing HD-induced myocardial stunning at either time point displayed elevated NTpro-BNP values (2,418 pg/ml, IQR, 1,583-3,474 vs. 1,751 pg/ml, IQR (536-2,029), p = 0.02). NTpro-BNP levels did not differ between patients showing HD-induced stunning at baseline and those developing stunning during the observational period (p = 0.8). NTpro-BNP levels drawn at the beginning of the dialysis session achieved a poor diagnostic accuracy for the detection of myocardial stunning (area under the ROC curve 0.61, 95% CI 0.45-0.77), but provided an accurate rule out for myocardial stunning during the subsequent year (AUC 0.85, 95% CI 0.70-0.99). The calculated cut-off of 1,570 pg/ml achieved a sensitivity of 66% and a specificity of 78% for the exclusion of myocardial stunning at any time point. In logistic regression analysis, only low NTpro-BNP levels (OR 0.92 for every additional 100 pg/ml, 95% CI 0.85-0.99, p = 0.03) were significantly associated with absence of myocardial stunning at any time point. Conclusion: Predialytic NTpro-BNP levels fail to adequately diagnose current dialysis-induced myocardial stunning, but help to identify patients with a propensity to develop dialysis-induced myocardial stunning at any time during the next 12 months.