Aghogho Odudu

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.

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.

Hemodialysis-Associated Cardiomyopathy: A Newly Defined Disease Entity

Cardiovascular disease is the most common cause of the greatly elevated rates of mortality characteristic of patients undergoing maintenance hemodialysis. This article is an attempt to describe the complex and evolving features of cardiac disease routinely encountered in HD patients. Furthermore, by trying to appreciate the pathophysiological drivers, and the crucial interaction with the HD treatment itself, this article seeks to define cardiac disease in this setting (HD‐associated cardiomyopathy) as a unique and complex entity. By understanding the phenotype and basis of HD‐associated cardiomyopathy, we can develop an evolved understanding of the dominant processes involved in its development and offer up dialysis‐based interventions specifically designed to mitigate the cumulative ischemic insults consequent to conventional HD treatment. This article explores the justification of this approach and recent evidence of its efficacy.

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

Modification of the Relationship Between Blood Pressure and Renal Albumin Permeability by Impaired Excretory Function and DiabetesNovelty and Significance

In animal models, reduced nephron mass impairs renal arteriolar autoregulation, increasing vulnerability of the remaining nephrons to elevated systemic blood pressure (BP). A feature of the resulting glomerular capillary hypertension is an increase in glomerular permeability. We sought evidence of a similar remnant nephron effect in human chronic kidney disease. In participants from the United States National Health and Nutrition Examination Surveys 1999 to 2010 (N=23 710), we examined the effect of reduced estimated glomerular filtration rate (eGFR) on the relationship between brachial artery BP and albumin permeability. Renal albumin permeability increased exponentially with systolic BP >110 mm Hg, and this association was modified by independent interactions with both excretory impairment and diabetes mellitus. Each 10 mm Hg increase in systolic BP was accompanied by an increase in fractional albumin excretion of 1.10-, 1.11-, 1.17-, 1.22-, and 1.38-fold for participants with eGFR≥90, 90>eGFR≥60, 60>eGFR≥45, 45>eGFR≥30, and eGFR<30 mL/min/1.73 m2, respectively, adjusted for age, sex, race, antihypertensive use, eGFR category, diabetes mellitus, smoking, history of cardiovascular disease, body mass index, and C-reactive protein. A 10 mm Hg systolic BP increment was associated with increases in fractional albumin excretion of 1.10- and 1.21-fold in nondiabetic and diabetic participants, respectively. Using urine albumin creatinine ratio as an alternative measure of albumin leak in eGFR-adjusted analyses gave the same conclusions. Our findings are consistent with the presence of a remnant nephron effect in human kidney disease. Future trials should consider the nephroprotective benefits of systolic BP lowering in kidney disease populations stratified by eGFR.

Volume is not the only key to hypertension control in dialysis patients

There is a widely held belief that hypervolaemia due to excess intake or inadequate removal of salt and water is the principal cause of hypertension in dialysis patients. The risk of failing to consider additional pathophysiological elements is that inadequate or inappropriate therapeutic strategies may be adopted. This review aims to highlight multiple alternative mechanisms for hypertension in this setting along with the risks of probing for normotension by empirical dry weight reduction if dry weight is imprecisely defined.

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.

MRI for the assessment of organ perfusion in patients with chronic kidney disease.

Purpose of reviewRecent data have highlighted the importance of quantitative measures of organ perfusion and functional reserve. Magnetic Resonance Imaging allows the assessment of markers of perfusion without the use of contrast media. Techniques such as arterial spin labelling (ASL) and blood oxygen level-dependent (BOLD) imaging have been available for some time, but advances in the technology and concerns over the safety of contrast media in renal disease have spurred renewed interest and development. Recent findingsASL measures perfusion, whereas BOLD imaging provides a marker of blood oxygenation, arising from the compound effect of a number of measures including perfusion, blood volume and oxygen consumption; thus, the techniques are complementary rather than analogous. They were initially confined to brain imaging as inherently low signal, susceptibility effects and motion limited their use in thoracic and abdominal organs. Advances in technology have led to robust sequences that can quantify clinically relevant changes and correlate well with reference standards. Novel approaches are likely to accelerate translation into clinical practice. SummaryThe noninvasive and repeatable nature of ASL and BOLD imaging makes it likely that they will be increasingly used in clinical research. Using a developmental framework, we suggest that the application of these techniques to thoracic and abdominal organs requires validation before they are suitable for generalized clinical use. The demand for these techniques is likely to be driven by the incentive to avoid the use of contrast media.