James O. Burton

Hemodialysis-Induced Cardiac Injury: Determinants and Associated Outcomes

BACKGROUND AND OBJECTIVES Hemodialysis (HD)-induced myocardial stunning driven by ischemia is a recognized complication of HD, which can be ameliorated by HD techniques that improve hemodynamics. In nondialysis patients, repeated ischemia leads to chronic reduction in left ventricular (LV) function. HD may initiate and drive the same process. In this study, we examined the prevalence and associations of HD-induced repetitive myocardial injury and long-term effects on LV function and patient outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seventy prevalent HD patients were assessed for evidence of subclinical myocardial injury at baseline using serial echocardiography and followed up after 12 mo. Intradialytic blood pressure, hematologic and biochemical samples, and patient demographics were also collected at both time points. RESULTS Sixty-four percent of patients had significant myocardial stunning during HD. Age, ultrafiltration volumes, intradialytic hypotension, and cardiac troponin-T (cTnT) levels were independent determinants associated with its presence. Myocardial stunning was associated with increased relative mortality at 12 mo (P = 0.019). Cox regression analysis showed increased hazard of death in patients with myocardial stunning and elevated cTnT than in patients with elevated cTnT alone (P < 0.02). Patients with myocardial stunning who survived 12 mo had significantly lower LV ejection fractions at rest and on HD (P < 0.001). CONCLUSIONS HD-induced myocardial stunning is common, and may contribute to the development of heart failure and increased mortality in HD patients. Enhanced understanding of dialysis-induced cardiac injury may provide novel therapeutic targets to reduce currently excessive rates of cardiovascular morbidity and mortality.

Hemodialysis-Induced Cardiac Dysfunction Is Associated with an Acute Reduction in Global and Segmental Myocardial Blood Flow

BACKGROUND AND OBJECTIVES Hemodialysis is associated with hemodynamic instability, acute cardiac ischemia, and the development of regional wall motion abnormalities (RWMAs). This study used serial intradialytic H(2)(15)O positron emission tomography scanning to confirm that the development of dialysis-induced RWMAs was associated with reduction in myocardial blood flow (MBF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Four prevalent hemodialysis patients without angiographically significant coronary artery disease had measurements of MBF during standard hemodialysis and biofeedback dialysis. All patients underwent serial measurements of MBF using positron emission tomography. Concurrent echocardiography was used to assess left ventricular function and the development of RWMAs. Hemodynamic variables were measured using continuous pulse wave analysis. RESULTS Mean prehemodialysis MBF was within the normal range. Global MBF was acutely reduced during hemodialysis. Segmental MBF was reduced to a significantly greater extent in areas that developed RWMAs compared with those that did not. Not all regions with reduced MBF were functionally affected, but a reduction in myocardial blood flow of >30% from baseline was significantly associated with the development of RWMAs. No significant differences in hemodynamic tolerability, RWMA development, or MBF between dialysis modalities were observed. CONCLUSIONS Hemodialysis is associated with repetitive myocardial ischemia, which, in the absence of coronary artery disease, may be due to coronary microvascular dysfunction. Stress-induced segmental left ventricular dysfunction correlates with matched reduction in MBF. Functional poststress recovery is consistent with myocardial stunning induced by hemodialysis. This process may be important in the development of heart failure in long-term hemodialysis patients.

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.

Hemodialysis-Induced Repetitive Myocardial Injury Results in Global and Segmental Reduction in Systolic Cardiac Function

BACKGROUND AND OBJECTIVES Hemodialysis (HD)-induced regional wall motion abnormalities (RWMAs) are common in HD patients and driven by ischemia. In nondialysis patients, repeated ischemia leads to chronic reduction in left ventricular (LV) function. HD-induced myocardial ischemia may initiate the same process. We examined the effect of HD-induced repetitive myocardial stunning on global and regional LV function. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS We analyzed data from 30 patients, previously identified as developing HD-induced myocardial ischemia. Serial echocardiographic assessments of global and regional LV performance were performed at baseline and repeated after 12 mo. RESULTS Several patients developed segments with a fixed reduction in systolic function of >60% after 1 yr. In this patient group, there was a significant reduction in resting LV ejection fraction (EF) from 61.5 +/- 10.1% to 52.9 +/- 8.6% (P < 0.007). Peak LV EF in response to dialysis also decreased from 59.5 +/- 10% versus 49.9 +/- 6.5% (P < 0.003), with a consequent increase in HD-induced hypotension (P < 0.0001). CONCLUSIONS HD-induced myocardial stunning may progress over 12 mo to the development of regional fixed systolic dysfunction, consistent with underlying myocardial hibernation and fibrosis. This may be an important and potentially modifiable process in the development of heart failure in HD patients.

Dialysis-Induced Regional Left Ventricular Dysfunction Is Ameliorated by Cooling the Dialysate

Dialysis patients who develop cardiac failure have a poor prognosis. Recurrent subclinical myocardial ischemia is important in the genesis of heart failure in nondialysis patients. It has previously been demonstrated that subclinical ischemia occurs during hemodialysis; therefore, this study examined whether the improved stability of cool-temperature dialysis lessens this phenomenon. Ten patients who were prone to intradialytic hypotension entered a randomized, crossover study to compare the development of dialysis-induced left ventricular (LV) regional wall motion abnormalities (RWMA) at dialysate temperatures of 37 and 35 degrees C. Serial echocardiography with quantitative analysis was used to assess ejection fraction and regional systolic LV function. BP and hemodynamic variables were measured using continuous pulse wave analysis. The severity of thermal symptoms was scored using a simple questionnaire. Forty-nine new RWMA developed in nine patients during hemodialysis with dialysate at 37 degrees C (HD(37)), compared with thirteen RWMA that developed in four patients during HD(35) (odds ratio 3.8; 95% confidence interval 2.1 to 6.9). The majority of RWMA displayed improved function by 30 min after dialysis. Overall, regional systolic LV function was significantly more impaired during HD(37) (P < 0.001). BP was higher during HD(35), with fewer episodes of hypotension as a result of a higher peripheral resistance and no difference in stroke volume. The development of thermal symptoms was heterogeneous, with most patients tolerating HD(35) well. This study confirms previous findings of reversible LV RWMA that develop during hemodialysis. It also shows that this phenomenon can be ameliorated by reducing dialysate temperature, a simple intervention with no cost implications.

Hemodialysis-Induced Left Ventricular Dysfunction Is Associated with an Increase in Ventricular Arrhythmias

Conventional hemodialysis results in intradialytic cardiac ischemia in a significant proportion of patients. Segmental myocardial ischemia results in the development of left ventricular regional wall motion abnormalities. Sudden death is the most common cause of mortality in hemodialysis patients. This study looked to examine any association between the development of left ventricular regional wall motion and cardiac arrhythmias. Forty established hemodialysis patients had 24-hour Holter recordings, which commenced immediately before a dialysis session. Frequency of isolated ectopy was classified as a percentage of the total beats on the Holter monitor record. Ventricular arrhythmias were stratified according to the Lown classification. Classes 3 and above were taken as complex ventricular arrhythmias. Patients also underwent baseline and intradialytic echocardiography to assess the development of concurrent regional wall motion abnormalities. Premature ventricular complexes and complex ventricular arrhythmias were both more common during hemodialysis than in the subsequent monitored period. Patients who developed regional wall motion abnormalities (n = 27) had significantly more premature ventricular complexes during hemodialysis than afterward (p < 0.001). Patients with ischemic heart disease and left ventricular hypertrophy both had a higher frequency of premature ventricular complexes during hemodialysis than those without (p < 0.03 and p < 0.02, respectively). Cardiac arrhythmias are common in hemodialysis patients. The frequency of premature ventricular complexes is significantly higher during hemodialysis in patients who develop regional wall motion abnormalities and may be related to factors associated with demand ischemia.

Pediatric Myocardial Stunning Underscores the Cardiac Toxicity of Conventional Hemodialysis Treatments

BACKGROUND AND OBJECTIVE In adults, hemodialysis (HD)-induced ischemia causes reversible myocardial dysfunction (myocardial stunning) that is progressive with raised attendant mortality. Children share an increased risk for death from a spectrum of uremia-related cardiovascular abnormalities but in the absence of significant classical atheromatous coronary artery disease; therefore, we elected to assess children who were on HD for the occurrence of myocardial stunning to investigate the relative importance of characteristic uremic cardiovascular abnormalities in the development of ischemic cardiac injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We included all single-center long-term HD patients (n = 12; range 2 to 17 yr), excluding those with structural cardiac disease. Patients underwent conventional thrice-weekly HD for 4 h using high-flux membranes. We measured regional left ventricle wall motion using serial echocardiography (before HD, during HD, and 15 min after HD). Significant stunning was defined as a 20% reduction in regional wall motion (RRWM) in two or more segments and hyperkinesis as an either >20 or >50% increase in shortening fraction (SF). RESULTS Eleven of 12 patients developed myocardial stunning with varying degrees of compensatory hyperkinesis in unaffected segments, maintaining left ventricular ejection fraction throughout HD. The mean segmental %SF([Overall]) and %SF([RRWM]) fell during HD (2.19 to 1.77 and 2.72 to 1.37, respectively). Intradialytic BP reduction was significantly associated with mean segmental %SF([RRWM]). CONCLUSIONS Children who receive conventional HD experience myocardial stunning. These data, in combination with previous adult studies of intradialytic myocardial blood flow, suggest a characteristic cardiovascular phenotype in HD patients that predisposes to significant demand ischemia.

Categorization of the hemodynamic response to hemodialysis: The importance of baroreflex sensitivity

Intradialytic hypotension (IDH) remains an important cause of morbidity and mortality in hemodialysis (HD) patients. The baroreflex arc is under autonomic control and regulates blood pressure. This study aimed to investigate the contribution of impaired baroreflex sensitivity (BRS) to the pathophysiology of IDH. Thirty‐four chronic HD (12 IDH‐prone, 22 IDH‐resistant) patients underwent BRS measurement during HD with relative blood volume monitoring. During analysis, patients were separated into four age‐matched groups according to resting BRS≥4.5 ms/mmHg and hemodynamic stability. Resting BRS was extremely heterogenous (geometric mean BRS 5.78±1.41 [range 1.76–41.41] ms/mmHg). Relative blood volume reduction was well matched in all groups (mean reduction in relative blood volume for all patients −6.74%±0.86%, P>0.05). Thirty‐seven episodes of IDH occurred in the IDH prone, reduced BRS group. Patients with impaired resting BRS and prone to IDH had markedly different responses to HD as compared to the preserved BRS group, but the total peripheral resistance response was significantly lower than in the IDH‐resistant patients (15.9%±2.1% vs. 42.4%±3.0%, respectively, P<0.001). In those patients prone to IDH and with impaired resting BRS, percentage reduction in cardiac output at the end of HD highly correlated with reduction in relative blood volume (r=0.94, P=0.006). Hypotension during dialysis may be an important source of recurrent cardiac injury and early recognition of those patients prone to relative symptomatic and asymptomatic hypotension remains important. Impaired resting BRS and recognition of a suboptimal peripheral pressor response, appear to predict those patients most likely to undergo hemodynamic instability and may assist in the pursuit of this elusive goal.

Association of anthropometric obesity measures with chronic kidney disease risk in a non-diabetic patient population

BACKGROUND Obesity is a risk factor for both chronic kidney disease (CKD) and cardiovascular disease. The association of simple indices of obesity with CKD remains poorly understood. Evidence suggests that measures of central obesity such as waist circumference (WC) and waist-to-hip ratio (WHR) are more accurate predictors of morbidity and cardiovascular risk than body mass index (BMI). This study aimed to investigate the association of BMI, WC and WHR with CKD risk in a population screened for type 2 diabetes. METHODS Data were drawn from a population-based screening programme of 6475 volunteers without pre-existing diabetes. A number of investigations and cardiovascular health-related assessments were performed. Participants were categorized into two groups: those with an estimated glomerular filtration rate (eGFR) ≥60 and <60 mL/min/1.73m(2). Participants were also categorized as low, medium and high risk according to each anthropometric variable. RESULTS CKD was independently associated with higher WC and BMI (P < 0.01) but not WHR (P = 0.47). Increasing obesity measured by BMI and WC was associated with a reduction in eGFR for both men and women (P < 0.001). Increasing risk categories for BMI and WC were also associated with lower eGFR in men and women (P < 0.001). Combining anthropometric measures provided no additional measure of risk for underlying CKD. CONCLUSIONS WC may be a simple and reliable clinical tool for the detection of underlying CKD within primary care. Given the complex interaction between adiposity and uraemia, a combined screening tool using BMI and WC or WHR is unlikely to provide any additional benefit to risk analysis.

Tissue-Advanced Glycation End Product Concentration in Dialysis Patients

BACKGROUND AND OBJECTIVES Tissue-advanced glycation end products (AGE) are a measure of cumulative metabolic stress. Assessment of tissue AGE by skin autofluoresence (AF) correlates well with cardiovascular outcomes in hemodialysis (HD) patients. This study aimed to measure and compare tissue AGE levels in HD and peritoneal dialysis (PD) patients and to evaluate the impact of systemic PD glucose exposure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Tissue AGE were measured in 115 established dialysis patients (62 HD and 53 PD) using a cutaneous AF device (AGE Reader; DiagnOptics). Values were compared with an age-matched non-chronic kidney disease database. Review of all previous PD solution delivery/prescription data determined PD glucose exposure. RESULTS PD patients were similar in age to HD patients but had a shorter dialysis vintage. There were no differences in ischemic heart disease or smoking history, statin or angiotensin-converting enzyme inhibitor (ACEi) use, lipids, biochemistry, or prevalence of diabetes. More than 90% of both groups had met current dialysis adequacy targets. Skin AF values in PD and HD patients were similar and strongly correlated with historical PD glucose exposure. Skin AF correlated with age in both groups but with dialysis vintage only in PD patients CONCLUSIONS Cumulative metabolic stress and transient hyperglycemia results in grossly elevated levels of tissue AGE in dialysis patients. In PD patients, this high level of AGE deposition is associated with historical glucose exposure. This observation provides a previously unappreciated potential link between PD exposure to glucose and systemic cardiovascular disease.