Chronic kidney disease (CKD) affects more than 20 million people in the United States, approximately 1 in 15 American adults. At the end of 2009, more than 600,000 people were being treated for end-stage renal disease (ESRD) and 485,000 patients had ESRD requiring renal replacement therapy.1 Patients with all stages of CKD have a high prevalence of cardiovascular morbidity, but the risk of cardiovascular mortality is highest in patients with ESRD, whose risk is 30 times greater than that of the general population.2–4
Among patients with ESRD, the leading cause of cardiovascular mortality is sudden cardiac death (SCD), which is defined as death resulting from the sudden, unexpected cessation of cardiac activity with hemodynamic collapse.2,5,6 SCD is the leading cause of death in hemodialysis patients. In the United States Renal Data System (USRDS) database, 26.9% of all-cause mortalities in prevalent dialysis patients from 2009 to 2011 were attributed to cardiac arrest or arrhythmias. The incidence of SCD in hemodialysis patients was 49.2 per 1000 patient-years in 2011, which is much higher than that of the general population.1–3 Consequently, treatment paradigms to prevent SCD in hemodialysis patients are of overriding importance.
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Although the risk of SCD among ESRD patients is well documented, it has not been ascertained whether this risk results primarily from the dialysis procedure or, alternatively, from a diminished glomerular filtration rate (GFR) per se. Why patients with CKD are at an increased risk for SCD remains speculative, but it is likely mediated—at least in part—by structural changes in the heart caused by CKD. The prevalence of left ventricular hypertrophy is especially high among patients with CKD.7 Patients with advanced CKD have “uremic cardiomyopathy,” a disorder which includes left ventricular hypertrophy, dilation, and systolic dysfunction;8,9 all of these derangements can obviously predispose to arrhythmias.
A decreased GFR has been proposed to cause endocardial as well as diffuse myocardial fibrosis that could enhance the risk of life-threatening ventricular arrhythmias and SCD.10 Clearly, these cardiac morphological changes could be the primary mediators of the kidney-associated risk of SCD.7-9
The pivotal abnormality that predisposes to the pathogenesis of arrhythmias and SCD is the abnormal myocardium, which is highly susceptible to abnormal ventricular conduction either spontaneously or via additional triggers. Based on this formulation, there are a number of noninvasive markers of myocardial vulnerability, including electrocardiogram (ECG) changes at rest or from ischemia, and alterations in dynamic ECG parameters which can be used to stratify persons at risk for sudden death and which could represent intermediate markers of SCD risk.10,11 Some of these ECG measures represent various mechanisms of developing life-threatening arrhythmias and include heart-rate variability (HRV), ventricular late potentials, and QT interval prolongation.
HRV is defined as the variation in RR intervals and serves as a surrogate marker of autonomic dysfunction.12 An alteration of the balance between sympathetic and parasympathetic tone by disease states can lead to depressed vagal tone and a resultant predominance of sympathetic activity, leading to tachycardia and cardiac electrical instability. In patients with CKD, sympathetic hormone levels are markedly elevated compared to healthy controls.13,14 Arterial hypotension during hemodialysis also leads to increased sympathetic activity. Depending on the particular study, there is a wide range of estimated prevalence of abnormal HRV in dialysis, from 16 to 76%.15–18 Severe or moderately depressed HRV is more common in patients receiving hemodialysis than in those on peritoneal dialysis.19–22
Alternatively, the risk of SCD in patients with CKD could also be mediated by dynamic metabolic and physiological changes that are known to be present. As detailed in Table 1, these changes include, but are not limited to: 1) the metabolic derangements of a uremic milieu, such as hyperkalemia, metabolic acidosis, anemia, and secondary hyperparathyroidism;1,23 2) electrophysiological abnormalities, such as triggered automaticity and ventricular repolarization abnormalities;13 3) transient functional changes that result from volume overload; and 4) a generalized microinflammatory state characterized by hypoalbuminemia, elevated homocysteine, and higher levels of serum inflammatory markers, which may contribute to arrhythmogenesis.24
Recently, Parekh and colleagues initiated the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, a prospective cohort study of patients recently initiated on chronic hemodialysis, with the overall goal of further elucidating arrhythmic and SCD risk.25 It is anticipated that the elucidation of modifiable risk factors for SCD in this study will help set the stage for future clinical trials to evaluate therapies aimed at preventing SCD in this high-risk population.
When CKD progresses to ESRD, hemodynamic variability and biochemical shifts associated with conventional renal replacement therapies such as hemodialysis could further predispose to additional SCDs. The next few sections of this paper will therefore focus on the complex interplay of the hemodialysis procedure itself with SCD.
Dialysis-related alterations in potassium and calcium as a trigger for SCD
Hemodialysis may act as an acute trigger for SCD in the dialysis setting, potentially due to rapid shifts in potassium, calcium, and fluid. In a study of 500 witnessed peridialytic sudden cardiac arrests (SCAs) vs 1600 matched control subjects, Pun and associates26 reported that the use of low potassium dialysate (< 2 mEq/L) was associated with a 2-fold increase in risk of SCA. The authors concluded that there was no evidence for a beneficial effect of low potassium dialysate even among patients with higher predialysis serum potassium levels.
In another recent study, Pun and colleagues27 reported that the use of low calcium dialysate and greater serum dialysate calcium gradients associates with a significantly increased risk of SCA. In a matched case control study of 2100 patients, there was a 50% increase in SCA risk with dialysate calcium < 2.5 mEq/L. The risk rose incrementally with increasing serum:dialysate calcium gradient. These observations emphasize the need for a prospective clinical trial to substantiate these associations. While we await the completion of such a clinical trial, a reasonable approach to counter SCD in vulnerable hemodialysis patients could be to reduce these risk exposures.
The medical community has known for some years now that the incidence of SCD is significantly greater in the 12 hours starting with the hemodialysis procedure and also in the last 12 hours of the interdialytic period (i.e., the 12 hours preceding the Monday or Tuesday dialysis28,29 ). This seminal finding suggests two parallel but different mechanisms of SCD in hemodialysis patients. The increased incidence starting with the actual hemodialysis procedure suggests a role for rapid fluid and electrolyte fluxes during the hemodialysis session itself and in the hours immediately after (on a background of some of the structural and metabolic abnormalities described above). The increased incidence in the last 12 hours of the interdialytic period would suggest a role for hyperkalemia, hypertension, and fluid overload.
Following on from this observation, a number of authors have established26,27 linkages between low potassium and calcium dialysate baths, for example, and SCD in hemodialysis patients, and also between low or high pre-dialysis potassium levels.
Relatively few analyses, however, have focused on a documentation of the specific type of cardiac arrhythmia in relation to both the dialysis cycle and the electrolyte and volume status of the patient. The use of implantable loop recorders allows for a continuous ECG recording and also an ability to “mark” when the patient felt symptomatic. It is likely that the data that are currently being acquired in studies such as the Monitoring in Dialysis (MiD) study30 will allow for an identification of the specific cardiac arrhythmias that are present in hemodialysis patients and also of their relationship to fluid and electrolyte fluxes.
The relevance of these findings has been a renewed interest in the impact of the hemodialysis prescription in the role of SCD in hemodialysis patients. For example, the realization that significant potassium flux as a result of low potassium baths––being used in the setting of high pre-dialysis potassium levels––has led to the near-universal abandonment of potassium dialysate baths less than 2 mEq/L. The concept of large serum-dialysate potassium differences has spawned another approach to reduce this gradient; namely, the potential use of the new class of potassium binders. One of these potassium binders (patiromer; Veltassa™; Relypsa; Redwood City, CA) is now available clinically, and the second binder (sodium zirconium cyclosilicate, or ZS-9; ZS Pharma; San Mateo, CA) is in late stages of development. The present authors postulate that treatment with these agents could enable a change in current clinical paradigms for hemodialysis patients—treatment would obviate the necessity for low potassium concentration in the dialysate baths because it would reduce high pre-dialysate potassium levels with a consequent reduction in electrolyte (potassium) fluxes (see Figure 1a).
Treatment with these new potassium binders may provide additional benefits in the dialysis setting (see Figure 1b). In particular, treatment with these agents could facilitate treatment with previously contraindicated agents, such as renin-angiotensin-aldosterone inhibitors (spironolactone, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers) in hemodialysis patients, with a consequent reduction in cardiovascular events. Another approach, of course, to potentially achieve the same goals could be the increased use of nocturnal hemodialysis.
Despite these advances, the present authors strongly believe that the medical community is still in its infancy with regard to modulating the hemodialysis prescription in an attempt to reduce SCD in hemodialysis patients. That there is an urgent need to do this is emphasized by a recent study authored by Pun and colleagues10 where they describe a significant additional risk for SCD in dialysis patients as compared to patients who have an estimated GFR < 15 but are not yet on dialysis (see Figure 2). In particular, we believe that it is critical to first identify the specific arrhythmic event that is responsible for SCD in these patients. While the traditional view has been that ventricular arrhythmias are the primary abnormality responsible for SCD, this paradigm may not hold true in the setting of SCD in hemodialysis patients. Indeed, early results from the MiD study30 suggest that bradycardias could also play an important role, as could the presence of undetected atrial fibrillation. Once these arrhythmias are identified, these events then need to be targeted, both through a tailoring of the dialysis prescription and through the use of drugs, devices, and—potentially—biologics; keeping in mind, of course, that therapies that target the cause of the arrhythmias and SCD (myocardial fibrosis and fluid and electrolyte fluxes, for example) are likely to be more effective than therapies that target only the arrhythmias (remember the Cardiac Arrhythmia Suppression Trial; CAST).31,32
Last, but not least, the present authors strongly believe that despite the challenges in addressing SCD in hemodialysis patients, there is an opportunity here to use the dialysis unit as the central hub to develop and test novel drugs, devices, and process-of-care interventions (including the modulation of the dialysis prescription) that target SCD. We bring our patients (who have high comorbidity burdens) into a relatively high-technology medical facility (the dialysis unit) three times a week, and we believe that we owe it to our patients to use the dialysis unit as the starting point for both clinical and process-of-care research and interventions that target these patients’ single most important cause of mortality—SCD.
Indeed, in a recent retrospective study that examined the risk of SCD in a large cohort of patients with chronic kidney disease, Pun and colleagues10 suggested that an additive risk is conferred by the dialytic procedure; in their study the SCD rate for dialysis patients far exceeded the SCD rate of patients who have an estimated GFR < 15 but are not yet on dialysis (see Figure 2).
Electrolyte variability and the pathogenesis of arrhythmias and SCD
Most patients with ESRD depend on intermittent hemodialysis to maintain levels of serum potassium and other electrolytes within a normal range. However, one of the challenges has been the safety of using a low-potassium dialysate to achieve that goal, given the concern about the effects that rapid and/or large changes in serum potassium concentrations may have on cardiac electrophysiology and arrhythmia.
In daily practice, in the management of patients with ESRD, dialysis adequacy is optimized and patients are advised to avoid potassium-rich food. Sometimes potassium-binding resins are used to increase gastrointestinal excretion of potassium. Furthermore, most patients receive hemodialysis with relatively low potassium dialysate (usually 2.0 mEq/L) to maintain the serum potassium concentration within a desirable range. Hyperkalemic patients with pre-dialysis serum potassium concentrations ≥ 5.0 mEq/L have longer survival times when they undergo hemodialysis against a low potassium dialysate.33 In contrast, the use of low potassium dialysate may lead to adverse electrocardiographic changes during and after hemodialysis.25,26,34 Several observational studies have indicated that hemodialysis against a low potassium dialysate might increase the risk of SCD, mainly in patients without pre-dialysis hyperkalemia.25,26,34 The utilization of low potassium dialysate in hemodialysis patients with pre-dialysis hyperkalemia, therefore, remains controversial.
Disclosures: Dr. Epstein is a consultant for Relyspa, Inc., Bayer HealthCare Pharmaceuticals, OPKO Health, Inc., and Novartis Pharmaceuticals.: Dr. Roy-Chaudhury is a consultant for Medtronic
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- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Renal Data USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD, 2005.
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