Sudden cardiac death and chronic kidney disease - International ...

International Journal of Cardiology 217 (2016) 16–27

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Sudden cardiac death and chronic kidney disease: From pathophysiology to treatment strategies L. Di Lullo a,⁎, R. Rivera b, V. Barbera a, A. Bellasi c, M. Cozzolino d, D. Russo e, A. De Pascalis f, D. Banerjee g, F. Floccari h, C. Ronco i a

Department of Nephrology and Dialysis, L. Parodi – Delfino Hospital, Colleferro, Rome, Italy Division of Nephrology, S. Gerardo Hospital, Monza, Italy Department of Nephrology and Dialysis, S. Anna Hospital, Como, Italy d Department of Health Sciences, Renal Division, San Paolo Hospital, University of Milan, Italy e Division of Nephrology, University of Naples “Federico II”, Naples, Italy f Department of Nephrology and Dialysis, Vito Fazzi Hospital, Lecce, Italy g Consultant Nephrologist and Reader, Clinical Sub Dean, Renal and Transplantation Unit, St George's University, London, UK h Department of Nephrology and Dialysis, S. Paolo Hospital, Civitavecchia, Italy i International Renal Research Institute, S. Bortolo Hospital, Vicenza, Italy b c

a r t i c l e

i n f o

Article history: Received 13 March 2016 Received in revised form 27 April 2016 Accepted 30 April 2016 Available online 3 May 2016 Keywords: CKD Cardiovascular mortality Cardiac arrhythmias Sudden cardiac death

a b s t r a c t Chronic kidney disease (CKD) patients demonstrate higher rates of cardiovascular mortality and morbidity; and increased incidence of sudden cardiac death (SCD) with declining kidney failure. Coronary artery disease (CAD) associated risk factors are the major determinants of SCD in the general population. However, current evidence suggests that in CKD patients, traditional cardiovascular risk factors may play a lesser role. Complex relationships between CKD-specific risk factors, structural heart disease, and ventricular arrhythmias (VA) contribute to the high risk of SCD. In dialysis patients, the occurrence of VA and SCD could be exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic overactivity, inflammation and iron toxicity. As outcomes in CKD patients after cardiac arrest are poor, primary and secondary prevention of SCD and cardiac arrest could reduce cardiovascular mortality in patients with CKD. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Cardiovascular diseases (CVD) account for approximately 50% of premature mortality observed in chronic kidney disease (CKD) patients. CKD affects approximately 13% of the adult population in the United States and the prevalence at any stage continues to rise as obesity, hypertension and diabetes increase in prevalence, together with population aging. The high burden of CKD contributes a large proportion of CV deaths seen in our population today. These patients are exposed to substantial hemodynamic stress and metabolic perturbations, which predispose them to cardiomyopathy, atherosclerosis, and arteriosclerosis with complex pathophysiological overlap between the heart and the kidney. Heart and kidney disease are common, often coexist, increase patient morbidity and mortality and lead to an increased cost of care. Recently, the Acute Dialysis Quality Initiative (ADQI) Working Group convened a consensus conference to develop a classification scheme

⁎ Corresponding author at: Department of Nephrology and Dialysis, L. Parodi – Delfino Hospital, 00034 Colleferro, Rome, Italy. E-mail address: [email protected] (L. Di Lullo).

http://dx.doi.org/10.1016/j.ijcard.2016.04.170 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

for the Cardio-Renal Syndrome (CRS) into five separate subtypes [1]. These CRS subtypes likely share pathophysiological mechanisms, but they also have distinguishing clinical features in terms of precipitating events, risk identification, natural history, and outcomes (Fig. 1). Elevated risk of CV morbidity and mortality in patients with CRS often precedes progression to end-stage renal disease (ESRD) and dialysis [2–4]. Sudden cardiac death (SCD) related mortality is increased 14-fold in dialysis patients when compared to subjects with a history of cardiovascular disease and normal kidney function; this feature had always been considered a complication of atherosclerotic disease [5]. Many authors have tried to identify SCD associated risk factors in CKD patients. Since a considerable proportion of cardiac deaths are not directly linked to myocardial infarction (MI), stroke, or chronic heart failure (CHF), other non-traditional risk factors are under investigation [5,6]. Kidney dysfunction has recently been considered as an independent risk factor for SCD, which has been adjudicated as a distinct endpoint in various cohort studies and clinical trials. The following review will report on the epidemiology, pathophysiology, and mechanisms of SCD in CKD patients and highlight current evidence regarding the use of pharmacological and non-pharmacological (device-based) therapies for SCD risk management.

L. Di Lullo et al. / International Journal of Cardiology 217 (2016) 16–27

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Fig. 1. Cardiorenal syndrome classification [1].

2. Epidemiology 2.1. Incidence of cardiac sudden death in general population SCD is a sudden, unexpected death caused by loss of heart function (sudden cardiac arrest). In general, SCD events are defined as those deaths that are either preceded by a witnessed collapse, or occur within one hour of an acute change in clinical condition, or occur within twenty-four hours since the deceased individual was known to be in his or her usual state of health [7]. It is the largest cause of natural death in the U.S. with estimated risk-adjusted incidence of sudden cardiac arrest of 76 per 100,000 per year (≈ 230,000 per year in the United States) [8]. Although we have seen major advances in cardiopulmonary resuscitation and post-resuscitation critical care in recent years, patient survival after cardiac arrest still remains poor. In the general population, SCD was recently estimated to be about 8% of the out-of-hospital cardiac arrests treated by emergency medical services personnel [9]. Unfortunately, the majority of SCDs occur at home, often in the absence of relatives or other witnesses. Accurate clinical identification of high risk patients is crucial for correct management, given the highlighted effectiveness of implantable cardioverter-defibrillators (ICD) in preventing SCD. About 50% of all coronary artery disease (CAD) deaths are sudden and unexpected, often occurring shortly after symptom onset [10]. As CAD represents the primary cause of both sudden and non-sudden cardiac deaths in the U.S. and Europe, the proportion of total cardiac deaths that occur suddenly is similar to the proportion of CAD-related sudden deaths. In addition, it is quite interesting that the age-adjusted decline in CAD mortality in the U.S. during the last decades has not affected number of sudden and unexpected coronary disease associated deaths [11,12]. Furthermore, the decreasing age-adjusted mortality does not imply a decrease in absolute numbers of SCD because of the growth and aging of the population, as well as the increasing prevalence of chronic heart disease [13,14]. Multiple clinical trials found that systolic left ventricular dysfunction associated with a reduction in left ventricular ejection fraction (LVEF) represented a fundamental diagnostic risk factor for SCD. This is currently the only recommended diagnostic and clinical criterion to identify higher risk patients who would benefit from prophylactic cardioverter-defibrillators (ICDs) for the primary prevention of SCD [15]. However, the systematic implementation of prophylactic ICD recommendations results in a substantial number of inappropriate ICD implantations and fails to prevent the majority of SCD occurring in the general population. Current international guidelines consider LVEF ≤35% as an indication for ICD implantation as the primary preventative measure in patients

with non-ischemic CHF [16]. However, although a reduced LVEF is considered a major risk factor for SCD, several other events occur in patients with LVEF N 35% [17]. Additionally, the relative risk of SCD is significantly higher in patients with LVEF ≤ 35% than in those with LVEF N35% but the absolute number of SCD cases is higher in patients with more preserved LVEF, as these patients represent a much larger subgroup. Data from The Maastricht Circulatory Arrest Registry indicate that, in patients for whom LVEF was measured before an SCD episode, 52% had LVEF N30% and 32% had LVEF N40% [18]. The authors found that CHF was only seen in a minority of the SCD population. Most SCD victims did not know they had heart disease or did not exhibit any of the variables consistent with poor left ventricular function. Interestingly, it was found that CAD, especially with previous myocardial infraction (MI), is frequently associated with SCD and the median time lapse between previous MI and SCD was nine years with a wide variation. 2.2. Incidence of SCD in CKD patients Definition of SCD could be problematic in CKD patients since deaths frequently occur at home and exact timing is often unknown. Therefore, other non-cardiac causes of sudden death, as well as cerebrovascular event, may contribute to global mortality in CKD patients. According to US Renal Data System [19,20], approximately 22% of all deaths are caused by SCD, and the incidence increases with age: 2% per year for ages 20 to 44 years, 3.7% per year for ages 45 to 64 years, and 7% per year for ages 65 years and older. These circumstances make CKD patients unique and as such, they should have a special consideration. In this context, sudden death occurring in the setting of missed hemodialysis treatment should not be considered SCD; it may be useful to differentiate SCD occurring in dialysis patients and SCD observed in non dialysis-dependent CKD patients. a) SCD in non dialysis-dependent CKD patients: Non-dialysis-dependent CKD patients are at increased risk of SCD, have a poorer prognosis following cardiac arrest compared to the general population, and the likelihood of survival decreases with a declining GFR. Few studies have evaluated the association between less severe reductions in kidney function, incidence of SCD and the benefit of prophylactic ICD therapy in CKD patients. In the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) [21], which included patients with previous MI and LVEF of ≤35% treated only with optimal medical therapy, the risk for SCD was increased by 17% for every 10 ml/min/1.73 m2 decrement in the estimated GFR (eGFR) [22]. In a similar way, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial [23] has confirmed

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the benefit of cardiac resynchronization therapy in reducing death and hospitalization in patients with advanced CHF but renal dysfunction was associated with a 67% greater risk of SCD during the follow-up period [24]. In this setting, however, it is difficult to discern whether CKD is just a marker of CHF severity or an independent predictor of SCD risk. Two recent observational studies have demonstrated an association between moderate kidney dysfunction and SCD risk in subjects with cardiovascular disease. In the first one, enrolling more than 2700 postmenopausal women with CAD participating in The Heart and Estrogen Replacement Study, the rate of SCD was higher in those patients with lower kidney function, and the presence of CHF and CAD could partially explain this association [25,26]. The second trial included a large cohort of CKD patients from the Duke Databank for Cardiovascular Disease [25,26] and has clearly shown that reductions in eGFR in CKD stage III–IV are associated with a progressive increase in risk of SCD in patients with CAD. However, the majority of these participants had a history of CAD, CHF or systolic dysfunction, and it is unclear whether chronic kidney dysfunction was just a marker of CVD or an independent predictor for SCD development. In a community-based study including more than 4400 ambulatory older adults, impaired kidney function was associated with increased risk of SCD [27]. In this study, the incidence of SCD events increased across cystatin C tertiles; elevated cystatin C concentration also captures a state of preclinical kidney disease that is highly prevalent among ambulatory older patients. A preclinical state of kidney disease refers to a specific condition that precedes the development of clinical disease and is associated with adverse health consequences [28]. Further analysis from this study showed that in patients without CKD (eGFR ≥60 ml/min per 1.73 m2) with elevated cystatin C levels (cystatin C ≥ 1.0 mg/l) there was a substantially increased risk for SCD events during the follow-up period. After multivariate adjustment, SCD risk was doubled in the preclinical kidney disease group compared with the normal kidney function reference group (creatinine-based eGFR ≥ 60 ml/min per 1.73 m2 and cystatin C b 1.0 mg/l). These findings suggest that even mild reductions in kidney function, demonstrated by higher cystatin C levels, increase the risk of SCD — particularly in susceptible populations such as elderly patients without any clinical evidence of CHF, CAD or systolic dysfunction [28] b) SCD in dialysis-dependent CKD patients:

SCD events comprise the majority of cardiovascular-related death in advanced CKD and 75% of dialysis patients who have a cardiac arrest do not survive. [29]. In a case–control study encompassing 43,200 HD patients, sudden cardiac arrest incidence was 4.5 events per 100,000 dialysis treatments during the three year study period [30]. In the USRDS database [30], the cause of deaths attributed to an arrhythmic mechanism is noted in the Centers for Medicare and Medicaid Services (CMS) death notification as either cardiac arrest/cause unknown or arrhythmia. Based on this definition, arrhythmias may therefore be responsible for 56% of all cardiac deaths or 25% of all-cause mortality in peritoneal dialysis patients, and 65% of all cardiac deaths or 27% of all-cause mortality in hemodialysis patients. Using more comprehensive death notification forms for annual data collection, including cause, context and location of death, and excluding deaths from sepsis, malignancy, hyperkalemia and withdrawal from dialysis, the USRDS Cardiovascular Special Studies Center (CVSSV) [30] has estimated that 29.7% of deaths in prevalent dialysis patients are related to SCD. The overall best current estimate is that SCD is accountable for 27 ± 2% of all-cause mortality in dialysis patients. Similar findings on the relative contribution (22 to 26%) of sudden death to all-cause mortality in dialysis patients have been reported in multiple studies including

HEMO [31], 4D trial [32], the CHOICE cohort [33], and the Dialysis Outcomes and Practice Patterns Study (DOPPS) [34]. The CVSSC [35] has also estimated that there was a slow, steady decline in the overall cardiac mortality rate between 2002 and 2011 in the US dialysis population (from 6.9% to 5.4% per year). The recent increase in the use of “evidence-based therapies” (such as betablockers) in dialysis patients could explain this phenomenon [36]. The first hemodialytic session of the week primarily accounts for SCD; compared with the average risk of SCD, there is a 50% increased frequency of SCD on the first hemodialysis session after the long weekend interval [37]. In addition, one study [38] reported that the SCD risk is increased threefold in the twelve hour period before the end of the long weekend interval and increased 1.7 times in the twelve hours following commencement of the dialysis procedure after this long interval (Fig. 2). High incidence of SCD over a five year longitudinal follow-up with a rate of 4.9% per year was also observed in a prospective cohort study [39] of Chinese patients receiving chronic peritoneal dialysis (PD). This observation is not surprising, given that PD patients are as likely to have kidney disease or uremia-related risk factors as hemodialysis patients. Finally, strong association between advanced CKD and SCD extends to the pediatric population as well. In a retrospective analysis that included nearly 1400 deaths among patients who started CKD treatment aged 0–30 years from the USRDS, cardiac arrests and arrhythmias comprised the majority of cardiac-related deaths, which occurred at a rate N2% per year [35,39]. These findings suggest the existence of other mechanisms different to atherosclerotic disease and CHF are responsible for triggering fatal arrhythmias in advanced CKD population. 3. Risk factors and pathophysiology of CKD — related SCD Pathophysiology of SCD in CKD is complex and results from overlap between transient events and underlying disease. In CKD patients, cardiomyopathy frequently occurs as a consequence of elevated ventricular pressure and volume. This adverse condition, which is likely exacerbated by rapid electrolyte shifts, divalent ion abnormalities, diabetes and sympathetic overactivity, predisposes CKD patients to electrical instability, ventricular arrhythmias, conduction abnormalities and cardiac arrest followed by hemodynamic collapse. Inflammation, iron deposition, impaired baroreflex effectiveness and sensitivity, as well as obstructive sleep apnea may also contribute to the risk of SCD (Fig. 3). 1. Uremic Cardiomyopathy: Left ventricular hypertrophy (LVH) has been shown to be a major predictor of SCD, independently of left ventricular systolic dysfunction related to essential hypertension or chronic ischemic heart disease [40]. LVH is common in CKD patients and increases as GFR falls [41]. At start dialysis, LVH is present in almost 75% of patients leading to left ventricular dilation [42–44] and associated with development of CHF [45]. Hypertension, anemia, volume overload and other risk factors can partly explain the progression of cardiac hypertrophy [46]. LVH has been reported to be a predictor of cardiac death in dialysis patients independent of arterial hypertension [47] and its progression has been clearly linked to risk of SCD through increased arrhythmogenesis and delay in ventricular depolarization and repolarization. In addition, regression of LVH with therapy has been reported to improve survival [48]. The molecular basis of LVH in uremic patients includes activation of growth factors, proto-oncogenes, plasma noradrenaline, cytokines and angiotensin II. These factors regulate intracellular processes that accelerate cardiac hypertrophy, myocardial fibrosis and apoptosis [49]. Both LVH and cardiac fibrosis has been implicated in increasing risk of sustained ventricular arrhythmias and predisposition to SCD [50,51]. The stimulus provided by dialysis treatment to ventricular arrhythmias is a well-known phenomenon. In the first large survey on the dialysis population conducted in 1988 [52], the incidence of ventricular


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Fig. 2. Timing of sudden cardiac death in hemodialysis patients. Graphical representation of the three hemodialysis sessions during the week. There are two short inter-HD intervals during the week and one long inter-HD interval during the weekend. Ratio of actual to expected number of occurrences of sudden death for each 12 h interval beginning with the start of hemodialysis. Modified from Bleyer AJ et al. Characteristics of sudden death in hemodialysis patients. Kidney Int. 2006; 69(12):2268–73.

arrhythmias was reported in 76% of cases. Dialysis treatment was reported as the most important arrhythmogenic factor, not only during the dialysis session but also several hours after the end of treatment. 2. Ischemic Heart Disease: In hemodialysis patients, CAD is likely to induce an arrhythmogenic effect, and the severity of coronary stenosis is associated with persistence of ventricular arrhythmias during and after the treatment [34,47]. In addition, the number of premature ventricular complexes (PVC) during and after hemodialysis session is higher in patients with CAD than in those without CAD [34,53].

A number of cardiac biomarkers were identified as predictors of outcomes in CKD patients. Cardiac troponins T and I (cTnT and cTnI)

represent markers for diagnosis of myocardial injury for all patients, including those with CKD, as they have a higher specificity and sensitivity for myocardial injury compared to the MB isoenzyme of creatine kinase (CK-MB) [54,55]. Higher cTnI levels were associated with higher risk of short-term cardiac outcomes among dialysis patients in three studies. Stable increased serum troponin levels also predict worse long-term cardiovascular outcomes and poor survival in asymptomatic CKD patients without AMI [56]. Others acute coronary syndrome markers, as well as brain natriuretic peptide (BNP), inflammatory markers, adhesion molecules, and asymmetric dimethylarginine (ADMA) can detect CKD patients at high risk of SCD [57]. Recently, prospective studies on cardiovascular outcomes in CKD patients employing new cardiac biomarkers of HDL dysfunction and/or

Fig. 3. Risk Factors and hypothesized mechanisms of sudden cardiac death in chronic kidney disease. Pathophysiology risk factors and hypothesized mechanisms of sudden cardiac death in chronic kidney disease patients: the interaction between transient events and underlying substrate.

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oxidative stress, have appeared in the literature: paraoxonase-1 (PON-1) [58] and ischemia modified albumin (IMA) [59]. PON-1 is a calcium-dependent esterase associated with HDL subfractions that contain apo A-I and clusterin, conferring protection against oxidative damage of various cells and lipoproteins. Low serum levels of PON-1 have been reported in HD and non-HD dependent CKD patients [60, 61], and its levels increase significantly after HD treatment [62]. In presence of myocardial ischemia, structural changes take place in the N-terminus of albumin, reducing its binding capacity for transitional metals. The effect is caused by albumin circulating through the ischemic capillary, especially in acute coronary syndromes [63]. IMA is thus considered as a CVD-related biomarker that is sensitive to myocardium ischemia [64]. Recent studies have shown significantly higher IMA levels in CKD patients compared to controls and further increased levels after HD treatment [65]. Despite the great attention paid to the roles of PON-1 and IMA as cardiac biomarkers the actual association to CKD is unknown. 3. Inflammation: Inflammation has been found to be associated with SCD independently of traditional cardiovascular risk factors [34]. Serum levels of proinflammatory cytokines increase with renal function decline [66]. High C-reactive protein (CRP) and cytokine (such as IL-6 and platelet-activating factor) levels have been associated with ventricular arrhythmias through the modulation of ion channel function [34,67,68] and sympathetic nervous system (SNS) hyperactivity. CRP and IL-6 were also associated with a doubled risk of SCD; in addition, a decrease in serum albumin level was associated with increased risk of SCD [34]. Premature atherosclerosis and cytokineinduced plaque instability could probably induce a direct effect on the myocardium and the electrical conduction system [34]. Myocardial fibrosis associated with an inflammatory process could also affect ventricular conduction, causing a delay in repolarization leading to ventricular arrhythmias and SCD [14,34]. In CKD patients, it has been shown that high levels of inflammatory mediators induce production of reactive oxygen species resulting in an accelerated vascular atherosclerosis and arterial calcification [41]. Accumulation of asymmetric dimethyl-arginine inhibits nitric oxide synthesis in endothelial cells, inducing endothelial dysfunction, vasoconstriction, and atherosclerosis [66]. Elevated levels of serum homocysteine (HCY) have been implicated in several heart diseases including CAD, CHF, acute MI, arrhythmogenesis and CHF. However, the underlying mechanisms are unknown. HCV is an agonist of the N-methyl-D-aspartate receptor present in cardiac tissue. Activation of this receptor increases intracellular Ca++ concentration leading to cell hyperexcitability. In addition, Hyc induces oxidative stress in myocardial cells and activates matrix metalloproteinases that degrade cell membrane proteins. High HCY levels are common in CKD patients and are associated with atherothrombotic events and incidents of cardiovascular mortality [68]. 4. Electrolytes' shifts, divalent ions abnormalities, QT interval and ventricular arrhythmias: rapid shift between extracellular and intracellular electrolyte concentrations during an HD session, depending on electrochemical gradient, leads to cellular membrane polarization exposing it to electrical instability. Calcium (Ca++) and potassium (K +) play an important role in maintaining electrical potential across the cellular membrane and their shifts have been carefully investigated [69] The heart rate-corrected QT (QTc) interval is a recognized ECG marker of the ventricular repolarization, and its prolongation has been associated with increased risk of arrhythmias. CKD can be associated with prolonged QT interval, which increase the risk of torsade de pointes; these conditions can represent risk factors for SCD [70]. Lengthening of the QTc interval is associated with several manifestations of uremic cardiomyopathy including LVH, left ventricular

dilatation, and reduced left ventricular ejection fraction [45,70]. In addition, more premature ventricular complexes (PVCs) occur during hemodialysis in patients with LVH compared with those without LVH [47]. In patients with CKD, especially in those undergoing dialysis treatment, prolonged QTc interval usually results from inappropriate myocardial depolarization and repolarization due to lengthening of potential duration that occurs secondary to LVH and intercardiomyocytic fibrosis [71]. Prolongation of QT interval [72,73], an increase of QT dispersion [74], and an alteration in the capacity to adapt QT interval to heart rate changes (QTc) have been reported during HD session [74]. Three Italian studies [75–77] showed a direct link between K+ concentration and QT interval prolongation. In these studies, complex arrhythmias were observed more frequently during and after HD session in those with a decreasing potassium profile compared with individuals whose potassium levels were kept constant. Data from patients treated at Fresenius Medical Care North America-affiliated centers [37,78,79] showed that dialysis with a K+ dialyzate concentration of 0 mmol/l or 1 mmol/l was a significant risk factor for SCD [79]. Using this prescription, cardiac arrests were more frequent than in controls (17.1% vs 8.8%; p b 0.0001), and they were prevalently observed during HD sessions carried out after a long interval between hemodialysis sessions, and less so in HD sessions following a short interval. Calcium homeostasis during a HD session can affect left ventricular relaxation. In HD patients, prolongation of QTc interval was inversely correlated with intradialytic variation of Ca++, suggesting that greatest reduction in Ca++ is associated with the greatest increase of QTc prolongation at the end of HD session [80]. These findings were confirmed by others [81]. In addition, hypocalcemia observed after the HD session correlated with a prolonged QTc interval and SCD even in patients without cardiovascular manifestations [73]. Greater QTc interval dispersion was associated with an increase in total and cardiovascular mortality in both hemodialysis and in peritoneal dialysis patients [82]. Intradialytic serum magnesium variations do not show an important role in QTc dispersion [83]. Hyperphosphatemia usually develops as kidney function declines [83,84] and it's usually associated with hyperparathyroidism, smooth muscle proliferation, vascular calcification, and coronary atherosclerosis [70]. Hyperphosphatemia-induced myocardial calcification could alter microcirculatory hemodynamics, raise extravascular resistance and threaten myocardial perfusion [85]. Hyperphosphatemia and elevated Ca ++ x PO4 product were correlated with an increase in the risk of death related to CAD and SCD [84,85]. In addition, SCD was also related to parathyroid hormone levels in a nonlinear model (U-shaped relationship) [85]. 5. Rapid fluid removal during hemodialysis: Ultrafiltration (UF), fluid removal during hemodialysis session by pressure and concentration gradient between the two sides of the dialyzer, plays a key role in maintaining circulating blood volume and patient's weight. Consequently, UF may contribute to an acute reduction of circulating volume, hypotension, tissue ischemia, maladaptive cardiac structural changes, arrhythmias and SCD [86,87]. Researchers are investigating associations between UF rate and all-cause and cardiovascular mortality in HD patients. However, the association between UF rate and CV mortality has been poorly studied at the present time. Some of the first evidence in this regard shows a small increase in all-cause mortality without an increase in cardiac mortality in patients undergoing a UF rate higher than 10 ml/h/kg [88]. Subsequent data suggesting that 10 ml/h/kg may be the cut-off point has been insufficient to observe a true UF rate associated CV mortality [89]. Using data from the HEMO study, including more than 1800 HD patients treated three times per week, UF rates were categorized as ≤ 10 ml/h/kg, 10–13 ml/h/kg, and N 13 ml/h/kg [87]. Compared


to UF rates ≤10 ml/h/kg, UF rates N 13 ml/h/kg were significantly associated with increased all-cause and CV mortality with adjusted hazard ratios (HR) of 1.59 and 1.71, respectively. An UF rate between 10 and 13 ml/kg/h was not significantly associated with greater allcause mortality and CV mortality. Only in patients with CHF, there was a significant association between this UF rate category and allcause mortality. Secondary analysis also showed that UF rate N13 ml/h/kg was significantly associated with a greater HR for the composite outcome of CV hospitalization and CV mortality, whereas UF rate 10–13 ml/h/kg was not. According to this data, higher UF rates are associated with greater CV mortality. During dialysis, fluid is removed directly from vascular space; when dialytic removal exceeds resorption from other compartments, circulating volume is reduced and transient myocardial ischaemia can result. This transient ischemia could result in myocardial stunning, which is an ischemia-mediated temporary reduction in cardiac function (i.e. regional wall motion abnormalities). Intradialytic recurrent myocardial stunning may over time lead to irreversible fibrotic changes and CHF, arrhythmias and SCD [90]. Following 70 HD patients without severe left ventricular dysfunction, McIntyre et al. observed a significant reduction in cardiac systolic function in more than 60% of patients [90]. Even in pediatric patients without arteriosclerosis, epicardial or small vessels disease, regional wall motion abnormalities during HD treatment occurred [91]. Thus, it appears that across the spectrum of age and CV risk profile, significant cardiac dysfunction occurs in a majority of HD patients. 6. Race and ethnicity: According to 2015 review on cardiovascular risk factor in CKD patients, prevalence of CVD seems to be higher in non – hispanic black (NHB) people than in non – hispanic white (NHW). Further statistical analysis indicated that NHB with estimate glomerular filtration rate (eGFR) 30–59.9 ml/min/1.73 m2 had significantly higher (worse) CVD Risk scores across all quantiles (Qs) than NHW. This race differences in CVD Risk were also significantly higher in NHB with eGFR 60–70 ml/min/1.73 m2 in Qs 1 and 2 as compared to their NHW counterparts. In conclusion NHB have a significantly higher CVD risk factor score in those with moderate and mild CKD than NHW. [92] 7. Other factors: In CKD patients, iron overload has been associated with elevated rates of hospitalization and mortality [93]. Iron can promote reactive oxygen species and free radical production resulting in intercardiomyocytic fibrosis [94]. High iron saturation was an independent risk factor for prolonged QTc dispersion in patients undergoing peritoneal dialysis [94] suggesting that iron overload could increase the risk of SCD due to conduction abnormalities in CKD patients. Patients with CKD are characterized by a tonic elevation of sympathetic tone. This factor largely contributes to their increased CV risk [95–97]. Augmented sympathetic activity is also seen during HD sessions, and usually subsides following bilateral nephrectomy, suggesting that this mechanism is volume-independent [96–98]. Sympathetic over-activity is usually secondary to an afferent signal from renal sensory nerves activating the sympathetic nervous system, resulting in norepinephrine release and enhanced sympathetic tone. The latter response could aggravate hypertension, ventricular hypertrophy, and heart failure, and result in increased risk of SCD [97]. Impaired arterial baroreflex sensitivity (BRS) is associated with an increased risk of ventricular arrhythmia and SCD [99]. The baroreflex effectiveness index (BEI), a novel index reflecting the number of times the baroreflex is active in controlling the heart rate in response to blood fluctuations, and is associated with cardiovascular outcomes in CKD. In stage 4–5 CKD patients with hypertension, both BRS and BEI were reduced compared with age-matched healthy controls [99]; reduced BEI was an independent predictor of all-cause mortality, while reduced BRS was an independent predictor of SCD [99]. However, both BRS and BEI can be considered markers providing prognostic information and clinical implication for CKD patients.

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4. Therapeutic strategies for preventing SCD There are few trials designed specifically to evaluate the efficacy of therapeutic interventions for SCD in the CKD population. The approach to reducing the risk of SCD in this group of patients is based on data obtained from other high-risk populations and subgroup analysis of clinical trials (Fig. 4). 4.1. Pharmacological drugs a) Beta-blockers: beta-blockers are anti-arrhythmic and anti-ischemic agents that reduce hospitalization, death and SCD risk [100,101]. However, the majority of randomized clinical trials (RCT) providing this evidence have excluded subjects with CKD. In a retrospective study, HD patients using beta-blockers had a lower rate of SCD [102]. Similarly, after multivariate analysis adjusting for comorbidities, blood results and dialysis parameters, the Dialysis Outcomes and Practice Patterns Study (DOPPS) found that beta-blockers were associated with lower risk of SCD [35]. In a recent metaanalysis evaluating the efficacy of beta-blockers in CKD patients with CHF, there was a 34% relative reduction in cardiovascular mortality in treated patients compared with placebo controls [103]. There is limited data about the effect of beta-blockers therapy in patients with CKD without CHF. An adequately powered prospective RCT assessing the effects of beta-blockers in both advanced CKD and dialysis patients is needed.

b) Calcium channel blockers (CCB): CCB may have potential cardioprotective effects by preventing coronary artery spasm, normalizing intracellular Ca++ concentration, limiting injury after cardiac arrest and preventing fatal arrhythmias [104]. While CCB may be beneficial for patients with CKD due to their antihypertensive effects, there is only limited data about the effects of CCB on SCD [105]. In a retrospective study [106], the administration of CCB led to a significant reduction in mortality of 67% in HD patients. After adjustment for case mix factors, tunneled catheters and concomitant medications, CCB treatment was associated with a significant survival advantage at twenty-four hours after cardiac arrest in outpatient hemodialysis clinics [106]. This data, therefore, suggests that dihydropyridine CCB may have a protective role in increasing survival post-cardiac arrest. c) Digoxin: Digoxin increases strength and efficiency of myocardial contractions, and is helpful in CHF treatment. It is used for cardiac rate and rhythm control through the inhibition of sodium-potassium ATPase activity and reduction of sympathetic tone. Two randomized controlled trials [107–109] have shown that the addition of digoxin did not improve survival in CKD patients, but rather increased cardiovascular death rates, probably linked to ventricular arrhythmias and fibrillation. The role of digoxin in HD patients would seem less controversial. The narrow therapeutic window, long half-life, and the potential risk for lethal arrhythmias, especially in the context of hypokalemia, are widely known. Because hemodialysis inevitably involves large potassium fluxes, digoxin and dialysis would seem to be a bad combination. In the largest study conducted to date including more than 120,000 HD patients from Fresenius Medical Care database [109], use of digoxin and increasing digoxin levels were associated with increased mortality. In addition, the mortality risk increases with low pre-dialysis potassium. Therefore, digoxin is unlikely to be a useful preventative therapy for SCD. d) Amiodarone: Amiodarone is a class III antiarrhythmic agent used for various types of cardiac dysrhythmias, both ventricular and atrial. It is an effective drug for prevention of SCD in the general population. A

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Fig. 4. Levels of intervention for the prevention and treatment of SCD.

meta-analysis of fifteen randomized controlled trials [110], conducted to evaluate efficacy of amiodarone vs. placebo/control for the prevention of SCD, reported a 29% reduction of the SCD risk in treated patients. However, amiodarone therapy is neutral with respect to all-cause mortality and is associated with a two- and five-fold increased risk of pulmonary and thyroid toxicity. As a result, amiodarone is no longer the first-line agent for arrhythmia control in the general population. No data exist for its use in dialysis patients specifically. Consequently, amiodarone is prescribed according with current guidelines for general population.

e) Renin-Angiostensin-Aldosterone System (RAAS) blockers: High aldoserone levels are reported to be an independent risk factor for SCD in non-CKD patients. Treatment with RAAS blockers increased survival in patients with CHF or MI [111,112]. The benefits of angiotensin-converting enzyme inhibitors (ACE-i) extend to patients with mild kidney dysfunction [113]. However, no equivalent data from randomized controlled trials exist for patients on dialysis. In the Fosinopril in Dialysis Trial (FOSIDIAL) [113], there was no reduction in cardiovascular events in the treated patients group. A further small open label RCT [114] investigated the effect of candesartan versus placebo in HD patients without cardiomyopathy. The study found a protective effect in the treated group with a reduction in CV events and CV mortality compared to placebo group. However, the study was inconclusive on the effects of candesartan on SCD. In the general population, the Randomised Aldactone Evaluation Study (RALES Study) [115,116], reported that Spironolactone reduced SCD by 20–30%, but dialysis patients were not included in this trial. In these patients, clinicians are cautious about using RAAS blockers to avoid hyperkalemia. However, in a systematic review [116] of six studies including more than 7000 dialysis patients with CHF, hyperkalaemic episodes were rare; mean serum potassium was 4.9 mmol/l and no patients developed an adverse event as a result of hyperkalaemia. f) Statins: Statins are known to prevent CV disease and improve lipid profiles however their effects in HD patients remained uncertain. A recent meta-analysis [117,118] including three randomized

controlled trials (4D, AURORA, SHARP) with more than 7000 HD patients, assessed the effects of statins compared to placebo in dialysis patients. This study showed that patients on dialysis treated with statins showed a modest benefit in terms of atherosclerotic CV events, but not for stroke and all-cause mortality. Similarly, in another meta-analysis [119] of twenty-one RCTs including 8186 dialysis patients, a benefit in reducing all cardiac events was observed, but no effect on CV deaths or all-cause mortality was reported. However, a Cochrane meta-analysis of 25 studies involving 8289 dialysis patients found no benefit of statin therapy on major CV events, cardiovascular mortality, all-cause mortality or myocardial infarction, despite efficacious lipid lowering [119]. In conclusion, statins had no impact on all-cause or CV mortality, but did show an improvement in CV events in dialysis patients.

4.2. Non-pharmacological options a) Implantable cardioverter defibrillator (ICD): According to the results of a meta-analysis [120], that combined the results of all three larger studies available in the general population, the first-line therapy for primary and secondary prevention of SCD is the inclusion of an ICD. However, major cardiovascular disease trials have excluded patients with CKD or did not provide adequate information on the renal function of enrollees or the effect of interventions on patients with renal disease. Since ICD therapy data in CKD patients are lacking, there is no general consensus on the use of devices in these patients. In non-dialysis-dependent CKD patients with CHF, ICDs appear to reduce mortality risk. A retrospective analysis from MADIT-II [22], showed a significant reduction in the risk of all-cause mortality and SCD risk in CKD patients with eGFR ≥ 35 ml/min per 1.73 m2 treated with ICD compared with those in the conventional therapy. However, no significant difference was found in both outcomes between the two treatment groups for patients with eGFR b 35 ml/min per 1.73 m2. Similarly, Alsheikh-Ali et al. [121] who had categorized patients according to the CHF-NYHA class and the CKD stage, observed the greatest benefits of ICD therapy in patients


clinically less compromised. These data suggest that SCD risk in patients treated with ICD and conventional therapy are equivalent in advanced stages of CKD and CHF. In dialysis patients hospitalized for ventricular fibrillation/cardiac arrest who received ICD implantation within thirty days of admission, Herzog et al. [122] observed a 42% reduction in overall death risk of death, concluding that ICD therapy improves survival in dialysis patients. However, the data for this retrospective study derived from Medicare claims, and important clinical data regarding systolic function, serum K + levels, CAD, and utilization of pharmacologic agents, were unavailable. In a study conducted on moderate to severe CKD patients with a LVEF b 35%, Khan et al. [123] observed that in patients who were not receiving dialysis, ICD therapy was associated with a better rate of survival, whereas in the group receiving dialysis, ICD placement did not impact survival. Differently from Herzog et al. [122], in this smaller study, survival analysis data was adjusted for clinical confounders such as CAD, CHF, hypertension, utilization of pharmacologic agents, eGFR, sex and race. The difference observed in survival according to dialysis therapy may depend on the presence of comorbidities that do not affect ICD therapy, the number of ventricular arrhythmias that could be reduced after ICD implantation, or the defibrillation threshold that may be increased in dialysis patients. In conclusion, the results from these studies and meta-analyses seem to indicate that the use of ICD therapy improves survival in CKD patient. Despite the high risk for ventricular arrhythmias and SCD in CKD patients, ICD therapy appears to be poorly applied. In the study from Herzog et al. [122] only 8% of eligible patients received an ICD, and other data [36] and studies [124,125] have also confirmed this evidence. In conclusion, the results from these studies and meta-analyses seem to indicate that the use of ICD therapy improves survival in CKD patients. However, prospective, randomized studies about ICD therapy in CKD patients are needed. To know more about the role of ICD therapy and confounding factors in dialysis patients, we must await results of the ICD2 trial [125]. b) Coronary revascularization: In patients with severe CAD, revascularization procedures appear to provide benefit over stand alone medical therapy. However, risk of long-term repeated revascularization, myocardial infarction, and SCD is greater in patients with CKD than in those with normal kidney function. Randomized studies [126–128] demonstrate comparable rates of death and myocardial infarction but higher rates of repeated revascularization in non-dialysis patients undergoing percutaneous coronary intervention (PCI) with bare metal stents (BMS) compared with coronary artery bypass grafting (CABG). CKD patients undergoing maintenance dialysis have been excluded from any randomized evaluation of the comparative efficacy of coronary revascularization strategies. Series of small retrospective studies have shown that long-term survival rates are higher in CKD patients who undergo CABG than in those who undergo PTCA [129–131]. In a large, retrospective study of the USRDS national database that compared CKD patients undergoing CABG with PTCA, a higher perioperative mortality rate in the CABG-treated patients (12.5% vs 5.4%) was observed [130]. However, surgical therapy was associated with a significant reduction in two and five year mortality, both all-cause death and cardiac death, compared to PTCA. Despite the introduction of drug-eluting stents (DES) in the majority of PCI procedures, which has resulted in a reduction in rates of restenosis and repeat revascularization, no survival advantage relative to BMS in the general population [131,132] has been demonstrated. A large cohort from US Medicare [133] reported a statistically significant mortality benefit associated with DES compared with BMS in dialysis patients. These findings were confirmed by a meta-analysis [133], where a significant reduction in repeat revascularization and a trend toward

23

reduced mortality was reported in DES compared with BMS treated dialysis patients. Another meta-analysis [134] evaluating CABG versus PCI concluded that existing data are inadequate to make a determination on the optimal strategy of coronary revascularization for dialysis patients. Thus, the optimal option for coronary revascularization in dialysis patients remains a matter of debate. c) Dialysis: Dialysis treatment is a remarkable cardiac stressor, continued indefinitely at a frequency of 3 times per week. In an effort to replace renal function every week in 12 h, hemodialysis is associated with a series of events that affect intra-dialytic hemodynamic stability caused by an acute reduction of circulating volume and leading to hypotension, collapse, tissue ischemia, maladaptive cardiac structural changes, arrhythmia, and SCD [135]. Since there is a threefold increase in SCD risk in the first hemodialysis session of the week [135], it is appropriate to point out two main areas where it is possible to act: dialysate and ultrafiltration. a. Dialysate: there is a well-established close association between dialysate K + concentration and QT interval prolongation with consequent risk of complex arrhythmias [76–78]. For this reason, dialysate K+ concentration is one of the most important parameters to investigate in reducing SCD risk during dialysis treatment. In a multivariate Cox regression analysis of HD patients [136], pre-HD hyperkalemia conferred a 2.7-fold increase in the risk of SCD. The optimal pre-HD serum K+ in respect of long-term survival was found between 4.6 and 5.3 mmol/l [137]. K+ dialyzate concentration from 0 mmol/l to 1 mmol/l is associated with increased risk of cardiac arrest [79]. However, it has also been reported that K + dialysate of b2 mmol/l (or b3 mmol/l if pre-HD serum K + is b 5 mmol/l) confers an increased risk of SCD [30]. Electrical repolarization is also dependent on Ca ++ handling. Low dialysate Ca++ levels is associated with increased QT dispersion and prolongation of QTc interval [80,81], suggesting a predisposition to ventricular arrhythmias even in patients without cardiovascular manifestations [73]. In a study that examined covariate-adjusted SCD risk associations with serum Ca++, several factors – dialysate Ca++, serum dialysate Ca gradient++, and low dialysate Ca++ – were associated with aberrations in cardiac conduction such as QT dispersion and QTc prolongation [138]. Thus, serum and dialysate Ca++, and serum-dialysate Ca++ gradients should be considered in determining the optimal dialysate Ca prescription. b. Ultrafiltration: High rates of fluid removal may result in intra-HD hypotension, myocardial stunning and injury, predisposing to arrhythmias or circulatory collapse. In the DOPPS study, a large UF volume (N 5.7% of post-dialysis weight) increased the risk for SCD [35]. A recent observational study reported that depressed heart rate variability (HRV) is associated with fluid overload in HD patients [139], and a strict fluid management plan resulted in an increase of HRV. Thus, the axis of HRV-UF may be one of the pathophysiological mechanisms by which fluid overload predisposes to arrhythmias. In selected patients in whom it is necessary to remove large volumes of fluid—such as those with pulmonary edema and large intra-dialysis weight gain, daily dialysis or nocturnal hemodialysis therapies can prevent prolonged myocardial damage by removing excessive fluid in a longer session. In a twenty-five article systematic review including patients undergoing daily-HD for almost three months [140], a decrease in systolic or mean arterial blood pressure was reported as the most significant outcome. Only two studies [141,142] reported a decrease in LVMI, and there were no studies available relating to mortality data. In a randomized controlled study [143], patients treated 2.5 h for six times a week, showed more favorable survival and decreased LVMI compared with those treated 3.5 h three times a week. Similarly, in a case control study [144], patients undergoing nocturnal HD showed better survival rates compared with patients

24


receiving conventional hemodialysis after two years of follow-up (19% vs 27% of mortality).

5. Conclusions Epidemiological data show that a quarter of HD patients will die from SCD. Risk factors for SCD are poorly understood among CKD patients. In the general population, CAD-associated risk factors represent the most important determinants of SCD risk, although among CKD patient there is evidence that these risk factors play smaller role. Prevention of SCD is crucial to improving survival in this patient group; unfortunately trials to test the benefits of therapies in any context tend to exclude patients with CKD. In addition, there is little evidence to support therapies used in the general population and then applied to HD patients. Indeed, available data for treatment in HD patient populations is usually derived from small post-hoc or observational studies. Regarding cardio-protective medications in HD patients, no single drug therapy has been shown to reduce the risk of SCD. However, retrospectives studies indicate that beta-blockers, CCB and RAAS blockers have been associated with a survival benefit after an arrhythmic cardiac arrest. Current evidence suggests that revascularization does not eliminate the risk of SCD in HD patients, and the major cause of postrevascularization death remains to be arrhythmias. Recommendations for revascularization should be made on an individual basis, and additional therapies may be needed to prevent SCD. CKD patients should not be excluded from receiving ICD implantation based on the indication for device therapy from current guidelines. However, the benefits of primary prevention from ICD implant in HD patients remains to be proven. Results of the ICD2 Trial are eagerly awaited, and may shed light on this topic. Dialysis treatment remains a considerable tool that clinicians can modulate in order to reduce the risk of SCD. The dialysate handling represents a determining factor: Both low potassium dialysate and extremes of serum potassium levels, as well as low calcium dialysate and large serum to dialysate calcium gradients, have been shown to increase risk of SCD It is also important to avoid excessive rates of fluid removal per HD session, as high UF volumes have been associated with SCD. Alternative prescriptions from conventional HD as well as short daily-HD or nocturnal-HD may be considered, especially for patients with several comorbidities or those with hemodynamic instability. Removing large amounts of fluid in patients with pulmonary edema and greater intra-dialysis weight gain through short daily-HD and/or nocturnal-HD can prevent hemodynamic instability, reduce prolonged myocardial damage, and decrease SCD risk. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Ronco, P. McCullough, S.D. Anker, I. Anand, N. Aspromonte, S.M. Bagshaw, et al., Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative, Eur. Heart J. 31 (6) (Mar 2010) 703–711. [2] R.N. Foley, A.M. Murray, S. Li, C.A. Herzog, A.M. McBean, P.W. Eggers, et al., Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999, J. Am. Soc. Nephrol. 16 (2) (Feb 2005) 489–495. [3] P. Muntner, J. He, L. Hamm, C. Loria, P.K. Whelton, Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States, J. Am. Soc. Nephrol. 13 (3) (Mar 1, 2002) 745–753. [4] P.S. Parfrey, R.N. Foley, The clinical epidemiology of cardiac disease in chronic renal failure, J. Am. Soc. Nephrol. 10 (7) (Jul 1, 1999) 1606–1615.

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