End stage renaldisease (ESRD), the final stage of chronic kidney disease (CKD) is the failureor near failure of the kidneys to perform their normal functions. 1 Thesefunctions include: excretion, maintenance of acid-base, fluid and electrolytebalance and the synthesis of hormones such as erythropoietin and renin. When a patient reaches ESRD,renal replacement therapy (RRT) in the form of dialysis or transplantation mustbe considered, as without treatment, symptoms will likely significantlydeteriorate within weeks or months.
There are two major forms of dialysis thatare available, i.e., HD(Hemodialysis) and peritoneal dialysis (PD).
They differ in terms of techniqueand physiology. HD requires vascular access while PDrequires peritoneal access. HDis an intermittent form of RRT that results in removal of toxins, electrolytes,and fluid in a periodic pattern, while CAPD is a continuous process. The choiceof modality depends on individual choice, patient’s abilities,medical problems, or geographic location. According toestimates, less than 20% of all long-term dialysis patients are on PD. The twofactors that were perceived to militate against PD were cost and high infectionrates. Cardiovasculardisease (CVD) is the leading cause of mortality among the patients on dialysis.
Dialysis may cause changes inhemodynamics, electrolytes, oxygenation, acid-base balance and autonomicbalance all of which are potentially arrhythmogenic. 2-5* USRDS-matched data shows that HDpatients during the first 06 months of therapy are at increased risk of SCD,may be because patients who are susceptible to adverse events on HD have theseevents early. After this initial period, the event rates for HD and peritonealdialysis (PD) merge up to 2 years, after which PD patients are more at risk(Rich et al 2006). 9* The early stagesaccount for most of the individuals with CKD but because individuals with anystage of CKD have a higher risk of cardiovascular disease morbidity andmortality than their risk of progression to ESRD, cardiovascular risk factormanagement in this group is critical. Unfortunately, fromIndia there is limited data available on the prevalence of CKD. Indian population-based study determined thecrude and age-adjusted ESRD incidence rates at 151 and 232 per millionpopulation respectively. 2 Diabetes mellitus and hypertension constitute over 2/3rd ofCKD cases in western countries. 11 In Indiatoo, diabetes and hypertension today account for as much as 40–60% cases ofCKD.
12 Standard hemodialysis isperformed three times a week, for 3–5 hours each session, with low-fluxmembranes. Since the 1960s there has been a general technical improvement indialysis machines, dialyzers, and dialysis solutions. These factors, as well asaccurate control of the ultrafiltration rate by new dialysis machines and moreprecise control of electrolyte dialysate composition, have improved hemodynamicstability during treatment. The substitution of acetate as the dialysate bufferwith bicarbonate has also improved vascular stability. The principle of hemodialysisis relatively straightforward. Blood flows on one side of a semi permeablemembrane, and dialysis fluid, an osmotically balanced solution of electrolytes,buffer, and glucose in water, flows on the other.
Despite all possiblemodifications, cardiovascular death rate among HD patients is extraordinarilyhigh 3. Peritoneal dialysisinvolves the instillation of dialysate into the peritoneal cavity to alloweffective dialysis to occur across the membrane lining the abdominal cavity.Peritoneal dialysis is continuous and fluid exchanges can either be performedmanually, usually four times a day (continuous ambulatory peritoneal dialysis,CAPD) or can be done automatically overnight (automated peritoneal dialysis,APD) which allows a greater number of fluid exchanges to be performed whilstthe patient sleeps. The frequency of fatal and non-fatal cardiovascular events isincreased even in the earliest stages of chronic kidney disease. 4-7 The analysis of USRDS database 8 extendingfrom 1977-1997 shows statistically significant alteration in HD group ofpatients as compared to CAPD patients; with maximum death rates on Monday in HDgroup and steady death rates were noted in patients using PD.
Jeloka et al 9 have shown that the cost of thecommonly prescribed HD and PD prescriptions are comparable. Fears of infectiondue to the hot, humid climate and poor hygienic conditions have also turned outto be unfounded; infection rates in most Indian PD programs are acceptable byInternational standards. Still, PD is seldom offered as a first-choice dialysistherapy, and only patients with multiple comorbidities not suitable for HD, areinitiated on PD.
Go et al determinedage standardized relative risk of cardiovascular events against eGFR (figure 1).Those patients with CKD stages 4 or 5 have the highest risk 10. figure-1 This risk is evenhigher within dialysis patients who display hugely elevated rates of cardiacmortality, at least thirty-times greater than age matched controls 3 In the HEMO study,the most common cause of death in dialyzed patients was ischemic heart disease(20.4 %) followed by cardiac rhythm disorder (10.4 %), cerebrovascular disease(8.
6 %), and infections (7.7 %) 13 According to theAnnual Report 2001 of the United States Renal Data System (USRDS), the incidenceof new myocardial infarction in the first year of renal replacement therapy was7.0 %, of cerebrovascular accidents 7.1 %, and of surgery for peripheralvascular disease 8.
4 % (Berger et al 1992). As a crudecomparison, the Framingham Heart Study reported that the annual risk ofre-infarction in subjects surviving a first recognized myocardial infarction was4 per cent per year, almost half the risk of new myocardial infarction in HDpatients 14 for whom the additional risk factor of uremia is compounded byalso being on dialysis. Such high levels ofcardiovascular disease in dialysis patients are in part due to the highprevalence of ‘traditional’ risk factors (diabetes, hypertension,hyperlipidaemia, smoking, and physical inactivity). Unfortunately, aggressivemanagement of these traditional risk factors in dialysis patients has failed toadequately control the progression of cardiovascular disease. For example, in uremicpatients, LV hypertrophy progresses with time on dialysis even when patientsare kept normotensive 15,16 In the study ofParfrey, 71 % of non-diabetic dialysis patients without dilated cardiomyopathyhad LV hypertrophy and in the majority of patients this progressed over aperiod of 3–4 years. Progression was not predicted by blood pressure, hyperparathyroidismor anemia (although these factors are definitely involved), suggesting thatadditional factors may play a part. Therefore this excess of cardiovasculardisease in dialysis patients must be explained by the presence of other uniquemetabolic and hemodynamic derangements specific to the uremic patient – the so called’uremic’ specific risk factors. These uremic risk factors are less well definedbut are multiple, including some of those mentioned above already.
It is not onlysystolic and diastolic blood pressures, which determine LV work and LV mass.Vascular calcification with increased vessel stiffness is common, associatedwith the development of left ventricular hypertrophy (LVH) 17 and also independentlypredicts mortality 18 Stiffening of theaorta and the associated increased impedance plays a major role in thedevelopment of LVH 19. High pulse pressure is a surrogate marker for aorticstiffness and pulse wave velocity is a potent predictor of LV mass andcardiovascular events 20,21. Diabetic patientswith ESRD have particularly high cardiovascular morbidity and mortality 22.Even diabetic patients without nephropathy have major abnormalities of cardiacstructure. In observational studies, when compared to non-diabetic individuals,diabetic patients have more severe LV hypertrophy and also develop ischemicheart disease more frequently.
23 Anemia is a commonconsequence of ESRD. Sustained anemia leads to vasodilatation, increased venousreturn, cardiac enlargement and increased cardiac output. 24,25 Numerousobservational studies documented that anemia is associated with increased LVmass in patients with CKD 26 and this is true even for apparently trivialdegrees of anemia. 27 Observational studies have also suggested that anemia isan independent predictor of mortality. 28,30 Partial correction of anemiapartly corrects LV hypertrophy 30-32 but there is little or no controlledevidence that reversal of anemia reduces cardiovascular mortality. In the Canadian Normalizationof Hemoglobin Trial, hemodialysis patients with asymptomatic echocardiographic enlargementwere randomly treated to hemoglobin of 10 or 13.
5 g/dl. The higher hemoglobinfailed to show a regression in left ventricular dilatation but subsequentstudies have shown that normal hemoglobin will prevent the development of newLV dilatation. 33 Recurrent volumeoverload with rapid fluid shifts (that occur on dialysis) increases cardiacfilling pressures and venous return, imposing an increased workload on the leftventricle. Eventually this increase in preload results in LV dilatation andLVH. A correlation is found between LV volume and blood volume. In patientswith fluid overload the heart diameters usually returns to normal a few hoursafter ultrafiltration, but chronic overload may lead to eccentric LV hypertrophyand irreversible dilatation. The importance of hypervolemiais illustrated by the observation of Ozkahaya et al. that volume control by lowsalt diet and aggressive ultrafiltration reversed LV dilatation and hypertrophydespite no administration of antihypertensive agents.
34,35 Cardiac mortality indialysis patients has also been linked to chronic inflammation, often manifestedas hypo albuminemia and elevated C-reactive protein (CRP) levels. Inflammationleads to accelerated atherosclerosis, vascular calcification and increasedmuscle catabolism. 36 Certainly, the elevation of several cytokines (inparticular CRP and interleukin-6) have also been shown to be associated with anincrease in mortality 37,38 The presence of LVHitself predicts a worse long term outcome, and is associated with an increasedpropensity to cardiac arrhythmias 39,40 LVH is more frequent in early stagesof chronic kidney disease and increases progressively, so that it is found inapproximately 70 per cent of patients starting renal replacement therapy.
41LVH is not an innocent academic finding: Silberberg et al. had clearlydocumented that it was an independent predictor of death on dialysis 42(figure-2) (figure-2) shows thatLVH reduces survival in dialysis patients. Cumulative survival according toechocardiographic LV hypertrophy defined as LV mitral inflow greater than 125g/m2. This cut-off point corresponds to the 95th centile of the normalpopulation. 42 It has long beensuspected that myocardial ischemia may be precipitated by hemodialysis, withthe first evidence of silent ST segment depression during dialysis reportingback to 1989. 43 However, this concept of dialysis induced subclinical ischemia(occurring without acute atherosclerotic plaque rupture) has receivedremarkably little attention, despite its theoretical plausibility.
Shortintermittent hemodialysis treatments exert significant hemodynamic effects, and20-30 per cent of treatments are complicated by intra-dialytic hypotension(IDH). 44-46 In conjunction with this, hemodialysis patients are particularlysusceptible to myocardial ischemia. In addition to the high prevalence ofcoronary artery atheroma 47,48 diabetic dialysis patients have been shown tohave a reduced coronary flow reserve (CFR) – the ability of coronary arteriesto dilate when myocardial demand is increased – even in the absence of coronaryvessel stenosis. 49 There is preliminaryevidence that the same phenomenon is also seen in non-diabetic dialysispatients 50 which may be due to LVH, that leads to both structural andfunctional reductions in the myocardial microcirculation. The presence of LVHon its own reduces coronary flow reserve (CFR) even in the absence of largevessel coronary disease. 51 Because of the increased extravasal resistance,coronary reserve is reduced as illustrated in the patient with aortic valvestenosis. They suffer from angina pectoris resulting from ischemia despitepatent arteries. This is particularly important in HD patients in whom ischemiais often asymptomatic.
52 Similarly the uremicpatient with LV hypertrophy may have ischemia intolerance when oxygen demand isincreased. In addition, the presence of concentric LVH renders the ventriclemore sensitive to acute changes in filling pressure, exactly as occurs during hemodialysis.53 Increased peripheral artery stiffness is also recognized to have anadverse effect on myocardial perfusion and reduces the ischemic threshold; 54therefore, LVH in conjunction with increased vascular stiffness leads to apropensity to reduced subendocardial blood flow. 55 Since the initial reportby Zuber et al 43, there have been further studies that have demonstratedsilent ST segment depression occurring during dialysis. 56-64 These studiesreport the occurrence of dialysis induced ST depression at rates that varybetween 15 and 40 per cent.
However, there has been ongoing debate as towhether these electrocardiographic abnormalities reflect silent ischaemia orchanges in electrolyte concentrations. Other than this, there has been only onesubsequent study that has demonstrated ischaemia using an alternate technique.Singh et al assessed dialysis induced ischaemia using sestamibi single photon emissioncomputed tomography (SPECT). 65 In an unselected group of ten dialysispatients who were not known to have coronary artery disease, seven developedperfusion defects during dialysis. Importantly, concurrent ST depressionoccurred with the perfusion defects in only 3 patients, suggesting that electrocardiographicassessment alone may underestimate the incidence of dialysis-induced ischemia. It has previouslybeen demonstrated that myocardial stunning occurs as a direct consequence of hemodialysis(and can be ameliorated by improving systemic hemodynamics whilst on treatment).
66,67 Therefore, if myocardial ischemia and stunning are induced by hemodialysisthen the process of hemodialysis itself, repeated three times a week, maypotentially contribute to chronic cardiac damage in this patient group.Myocardial stunning is therefore increasingly thought to be an underappreciatedcausative mechanism for heart failure in the hemodialysis population. Altered renalfunction in CKD itself deregulates cardio-renal axis causing cardiac remodelingwhich results in a widespectrum of arrhythmias like supraventricular tachycardia, atrial fibrillation,ventricular ectopic beats, ventricular tachyarrhythmia, and sudden cardiacdeath (SCD). 6* Suddencardiac death appears to correlate with the peri-dialytic period. 68Consequently, there have been a number of studies looking at the potentialpro-arrhythmogenic effects of HD, which reported the frequency of dialysisinduced arrhythmias as anywhere in the range of 5 – 75% of treatments. 69,70The presence of both potentially life threatening complex ventriculararrhythmias (CVAs) and premature ventricular complexes (PVCs) has beenassociated with increased morbidity and mortality. CVAs (defined as Lown score100* of 3 and above) are reported in up to 35% of HD patients duringtreatment 56 and associated with negative prognostic factors including newcoronary events 104 and silent myocardial ischemia.
60 In the generalpopulation, people with PVCs are more than twice as likely to die from coronaryartery disease (CAD)71 and their presence may play a vital role in assessmentof cardiovascular risk. The frequency and prevalence of intra- andpost-dialytic ventricular arrhythmias are higher in patients with significantcoronary stenosis; 72 suggesting that myocardial ischemia plays a direct rolein the induction and persistence of ventricular arrhythmias during and afterHD. Myocardial ischemia is also known to leadto the development of regional wall motion abnormalities (RWMAs) and myocardialstunning as a direct consequence of HD.
73,74 This arises secondary toischemia caused by a reversible reduction in myocardial blood flow during theHD treatment session even in the absence of significant CAD. 75 In additionHD patients have been shown to reduce coronary flow reserves, 49 increasedprevalence of left ventricular hypertrophy and impaired microcirculation 76,all of which predispose to demand myocardial ischemia. A number of therapeuticstrategies directly targeting the increased incidence of CVAs and PVCs in HDpatients have been utilized. Unfortunately the majority of these involveadditional pharmacological agents that may be poorly tolerated and haveundesirable side-effects.
77 No evidence currentlyexists that myocardial ischemia may contribute to the development of both RWMAsand ventricular arrhythmias. As ischemia induced RWMAs are potentiallypreventable, 66,67 the identification of a common pathophysiological processconnecting both sudden and ischemic cardiac death in dialysis patients mayoffer single therapeutic targets to reduce both causes of mortality. Intra-dialytichypotension (IDH) is a very serious clinical problem and remains a significantcause of morbidity in the HD population, occurring in 20-30 % of treatments78.
In addition, a fall in blood pressure during dialysis predicts mortality.77 Furthermore, IDH could potentially contribute to myocardial hypoperfusionduring dialysis. The main mechanism of IDH is rapid reduction of blood volume owingto ultrafiltration and decrease in extracellular osmolarity during the dialysissession. If the ultrafiltration rate exceeds the plasma refill rate, this willlead to a reduction in circulating volume. Hypotension occurs when thisreduction in blood volume surpasses the compensatory mechanisms of thecardiovascular system. Various studies have shown that patientson HD are more prone to life threatening arrhythmias as compared to patients onPD. Hence ECG changes in these patients undergoing dialysis do have aprognostic significance.
Though several studies have investigated ECG changesand arrhythmias in dialysis patients, very few compare thedifferences in these changes in patients on HD vis-a-vis peritoneal dialysis.