Cardiovascular morbidity and mortality in patients treated with hemodialysis – epidemiological analysis

Background/Aim. Cardiovascular diseases are the leading cause of death in patients treated with hemodialysis (HD). The annual cardiovascular mortality rate in these patients is 9%. Left ventricular (LV) hypertrophy, ischemic heart disease and heart failure are the most prevalent cardiovascular causes of death. The aim of this study was to assess the prevalence of traditional and nontraditional risk factors for cardiovascular complications, to assess the prevalence of cardiovascular complications and overall and cardiovascular mortality rate in patients on HD. Methods. We investigated a total of 115 patients undergoing HD for at least 6 months. First, a crosssectional study was performed, followed by a two-year followup study. Beside standard biochemical parameters, we also determined cardiac troponins and echocardiographic parameters of LV morphology and function (LV mass index, LV fractional shortening, LV ejection fraction). The results were analyzed using the Student's t test and Mann-Whitney U test. Results. The patients with adverse outcome had significantly lower serum albumin (p < 0.01) and higher serum homocystein, troponin I and T, and LV mass index (p < 0.01). Hyperhomocysteinemia, anemia, hypertriglyceridemia and uncontrolled hypertension had the highest prevalence (86.09%, 76.52%, 43.48% and 36.52%, respectively) among all investigated cardiovascular risk factors. Hypertrophy of the LV was presented in 71.31% of the patients and congestive heart failure in 8.70%. Heart valve calcification was found in 48.70% of the patients, pericardial effusion in 25.22% and disrrhythmia in 20.87% of the investigated patients. The average annual overall mortality rate was 13.74%, while average cardiovascular mortality rate was 8.51%. Conclusion. Patients on HD have high risk for cardiovascular morbidity and mortality.


Indtroduction
Cardiovascular diseases are the leading cause of death in patients on hemodialysis (HD).The annual mortality rate from cardiovascular disease in these patients is 9%.The major cardiovascular complications are left ventricular (LV) hypertrophy (LVH) (75%), ischemic heart disease (40%) and congestive hart failure (40%) 1 .High incidence of cardiovascular disease in patients on HD is related to high prevelence of traditional (hypertension, disturbed lipid metabolism, diabetes mellitus, cigarette smoking) and nontraditional (microinflammation, oxidative stress, hyperhomocysteinemia, secondary hyperparathyroidism) risk factors, which lead to increased atherosclerosis, plaque destabilization, myocardial fibrosis and valvular heart disease 2,3 .
Patients on hemodialysis are at higher risk for sudden cardiac death 4 .Hypertrophy of LV (present in 75% of patients on HD), fast electrolyte changes during HD (absence of potassium in dialysis solution), hyperkalemia, myocardial fibrosis and decreased coronary perfusion, all contribute significantly to the appearance of sudden cardiac death in these patients 4 .
The aim of this study was to determine the prevalence of traditional and nontraditional (metabolic and hemodynamic) risk factors for the development of cardiovascular complications in patients on HD.Furthermore, we aimed to determine the prevalence of cardiovascular complications and overall and cardiovascular mortality rate in patients on regular HD.

Methods
This study was conducted at the Department of Hemodialysis, Clinic for Urology and Nephrology, Clinical Center of Kragujevac at Kragujevac, Serbia.The study included 115 patients (71 males and 44 females).All patients gave informed consent for participating in the study, according to the Declaration of Helsinki.All subjects were hemodynamically stable and on standard bicarbonate HD for over 6 months, with diuresis < 200 ml/24 h and had various primary renal diseases.

Laboratory analysis
Blood samples for laboratory analyses were drawn after 12 hours overnight fasting, before the dialysis session and heparin administration.
Hemoglobin concentration was measured by colorimetry, standard range was 110-180 g/l.Hematocrit was determined automatically with COULTER ® A C apparatus and from the formula: Hct(%) = (RBC × MCV)/10, where RBCred blood cells and MCV -mean cell volume.Normal range was 0.35-0.60.
Serum albumin level was measured by photometric colour test with bromcresol green.The normal range was 38-46 g/l and concentration < 36 g/l suggested malnutrition.
Serum cholesterol was determined with enzymatic method (cholesterol esterase -cholesterol oxidase).Reference range was 3.37-6.48mmol/l.Serum HDL lipoproteins concentration was measured by colorimetry.Reference range was 0.78-1.55mmol/l.Serum LDL concentration was calculated from the formula: C LDL = C HOL-tot -(TGL/2.2) -C HDL , where C LDL is serum LDL concentration, C HOL-tot is total serum cholesterol , C HDL is serum HDL concentration and TGL is serum triglycerides concentration.Reference range for LDL cholesterol was 2.39-4.08mmol/l.Serum triglycerides were determined by enzymatic colorimetric method, normal range is 0-1.88 mmol/l.Serum lipoprotein (a) concentration was determined by the Behring Nephelometer System and N Latex Lp(a) reagent.Levels < 30 mg/dl were considered normal.Serum apolipoprotein AI (ApoAI) and apolipoprotein B (ApoB) levels were determined with N Antiserum to Human ApoAI (ApoAI) and N Antiserum to Human ApoB reagents respectively.Normal range for ApoAI was 1.25-2.15g/l (women), 1.10-2.05g/l (men), for ApoB was 0.55-1.25 g/l (women), 0.55-1.40g/l (men).Reference range for apoB/apoAI ratio was 0.30-0.90g/l for women and 0.35-1.00g/l for men.
Serum calcium concentration was determined by photometric color test (Arseniko), reference range being 2.20-2.65 mmol/l.Serum phosphate was determined by photometric ultraviolet (UV) test, normal range being 0.80-1.45mmol/l.Serum iPTH was determined by radioimmunoassay (IRMA).Normal iPTH concentration is 11.8-64.5 pg/ml for healthy individuals.Target levels for pateints on HD are below 200-300 pg/ml.
Homocystein concentration was measured by Fluorescence Polarization Immunoassay (FPIA) method.Levels > 15 μmol/l indicated hyperhomocysteinemia. Serum CRP was determined using the immunochemical nephelometric method, and calculated as mean value of two measurements in three months.Normal value was ≤ 5 mg/l.
Measurement of serum cardiac troponin T (cTnT) was based on electrochemiluminescence immunoassay technology (ElektroChemiLumineszenz ImmunoAssay -ECLIA method), by using the Roche Diagnostics troponin T kit.A level of > 0.1 ng/ml was considered positive for myocardial necrosis.Serum cardiac tropinin I (cTnI) was determined with ADV A × SYM cTnI immunoassay technology (Abbott laboratories).A level of > 0.15 ng/ml was considered positive for myocardial necrosis.

Echocardiography
The echocardiocraphic study was performed 15 to 20 hours after the dialysis session, in order to avoid enddiastolic LV diameter alterations induced by the interdialytic volume gain.All studies were performed on a SHIMADZU-2200 ultrasound machine, with a 2.5 megahertz (MHz) transducer probe, by a single experienced physician.
Arterial blood pressure was calculated as average value of twelve monthly measurements prior to laboratory and echocardiographic investigations.Hypertension exists when arterial BP is ≥ 140/90 mmHg in patients treated with antihypertensive drugs.
Arteriovenous shunt blood flow was determined with colour flow Doppler ultrasound, just before echocardiographic examination, on SHIMADZU-2200 machine, using the 7.5 MHz probe.Arteriovenous shunt blood flow was calculated as mean of three measurements on efferent vein, each performed 2-4 cm proximally to anastamosis.Target Q AV for adequate dialysis is 300-800 ml/min.

Clinical definition of cardiovascular morbidity and mortality
Heart failure was characterized with presence of dyspnea and two of the following parameters: increased jugular venous pressure, rales, pulmonary hypertension or interstitial pulmonary edema confirmed on chest radiography 8 .
Ischemic heart disease was defined as the presence of angina pectoris and/or a previous myocardial infarction.According to the American College of Cardiology and European Society of Cardiology myocardial infarction is characterized with spontaneous chest pain lasting over 20 minutes, accompanied by rise in cTnI level (cTnI ≥ 2 ng/mL), ST segment elevation ≥ 0,2 mV in leads V2-V3, or ≥ 0,1 mV in other leads, or presence of Q wave ≥ 1 mm and ≥ 30 ms wide in at least two consequent leads.De novo left bundle brunch block can also be a sign of acute myocardial infarction 8 .
Infectious endocarditis was diagnosed based on the presence of either two major or one major and 3-5 minor Duke's criteria.The major criteria are: at least two positive blood cultures, new valvular regurgitation, positive echocardiogram (oscillating intracardiac mass on valve or supporting structures).The minor criteria include: patient predisposition, fever, vascular phenomenon, immunologic phenomenon, microbiological evidence (one positive blood culture) and echocardiographic finding consistent with infectious endocarditis but do not meet a major criterion as noted above 9,10 .
Causes of death in patients on HD were classified as cardiovascular events (acute myocardial infarction, congestive heart failure and sudden death) and non-cardiovascular events (infection/sepsis, neoplasm, unknown) 11 .

Statistic analysis
Results were statistically analyzed with Student′s t test and Mann-Whitney U test.Values < 0.05 and < 0.01 were considered significant.

Results
Average age of 115 investigated patients was 53.30 ± 12.17 years, average time on dialysis 4.51 ± 4.01 years and average single pool modeling fractional clearance of body water of urea (Kt/Vsp) -Kt/Vsp 1.17 ± 0.23.General patients' data are shown in Table 1.
According to the results of a two-year follow-up period the patients were separated in two groups, 86 alive persons and 29 deceased.The patients with adverse outcome had significantly lower serum albumin levels and significantly higher serum tHcy, cTnT, cTnI and LVMi (Table 2).
Table 3 shows the prevalence of traditional risk factors for the development of cardiovascular complications in patients on HD.Hypertriglyceridemia (43.48%) and unregulated hypertension (36.5%) were the most prevalent risk factors in our group.Table 4 shows the prevalence of non-traditional risk factors for cardiovascular complications in patients on HD.Hyperhomocysteinemia and anemia had the highest prevalence (86.09% and 76.52%, respectively).
The prevalence of LV morphology alterations is shown in Table 5. Left ventricular hypertrophy was present in 71.31% (82) of the patients, while only 14.78% (17) had normal LV morphology.Disturbed systolic function, accompanied by symptoms and signs of congestive hart failure, was present in 8.70% of the patients, as shown in Table 6.
Left ventricular hypertrophy is a strong predictor of cardiovascular morbidity and mortality in patients on HD 24 .Increase of LVMi by ≥ 1,0 g/m 2 /month is associated with increased risk of cardiovascular complications 24 .Left ventricular hypertrophy was present in 71.31% of our patients on HD.Similar rate of LVH on HD was reported by other authors [25][26][27] .In patients with normal LV volume (iEDV ≤ 90 ml/m 2 ) and normal systolic function (LVFS > 25%, LVEF > 50%), LVMi > 120 g/m 2 and LVMi/iEDV > 2.2 g/ml are independently associated with late mortality (death > 2 years following start of HD treatment) 28,29 .Timely detection of risk factors and adequate treatment enable regression of LVH in patients on HD 30 .
Aortic valve calcification is present in 28-58% of treated with patients on HD, while mitral valve calcification was found in 24%, as reported in previous studies 31 .In our study group, aortal valve calcification was found in 33.91% of patients and mitral valve calcification in 14.79%.Aortic valve calcification is associated with high peak transaortic blood flow, values ≥ 2.5 m/s indicating aortic stenosis 31 .Patients' age, time on dialysis, hyperphosphatemia and high calcium-phosphate product significantly contribute to the development of aortic valve calcification 31 .The annual incidence of hemodynamically significant aortic stenosis in patients on HD is 3.3% 32 .Aortic valve calcification leads to aortic stenosis, LV pressure overload and concentric LVH 31,32 .Long term LV pressure overload caused by aortic stenosis leads to progression of LVH from adaptive to maladaptive stage, development of cardiomyopathy, myocyte loss and heart failure 32 .Mitral valve calcification causes left atrial dilatation and atrial fibrillation (absolute arrhythmia) 33,34 .Secondary hyperparathyroidism, hyperphosphatemia and high calcium-phosphate product are associated with calcification of heart valves, coronary arteries and increased cardiovascular mortality 33,34 .
Intermitent atrial fibrillation is present in 16% of patients on HD 35 .It usually appears during HD session and stops spontaneously without therapeutic intervention 2-3 hours after the HD session.Propafenone was used successfully in both acute atrial fibrillation and as a prophylactic agent in patients on HD 36 .
The prevalence of symptomatic pericardial disease in patients treated with HD is 11.8-21%.Mortality rate due to pericardial disease is 1.5% 37 .Pericardial effusion was present in 25.22% of our patients, while 3.48% of them had clinically significant effusion.Risk factors for development of pericarditis and pericardial effusion in end-stage renal disease patients are uremia, volume overload, malnutrition, inadequate HD, uncontrolled secondary hyperparathyroidism, high calcium-phosphate product and infection 37 .
Risk factors for heart arrhythmia in patients treated with HD are: ischemic heart disease, LVH, congestive heart failure, pericardial effusion and electrolyte dysbalance 38 .The prevalence of atrial disrrhythmia in end-stage renal disease patients on HD is 6%, atrial fibrillation being the most common 38 .Ischemic heart disease, LVH and mitral valve calcification are the most often correlated with atrial fibrillation 38 .The prevalence of ventricular extrasystole in our study group was 5.22%, and the prevalence of persistent atrial fibrillation was 4.35%.Congestive heart failure, ventricular disrrhythmias, sudden cardiac death and acute myocardial infarction account for at least 40% of cardiovascular deaths in patients on HD 39 .The annual overall mortality rate in patients on HD is 6-16% and the annual cardiovascular mortality rate is 9% 39 .Our results show that annual overall mortality rate is 13.74% and average annual cardiovascular mortality rate is 8.51%.These results correspond with the mentioned published data 39 .
The strategy for lowering overall and cardiovascular mortality in patients on HD should include identification and selection of high-risk patients, permanent evaluation of dialysis adequacy, maintaining better hemodynamic stability and electrolyte balance, and constant evaluation of prescribed cardioprotective therapy [39][40][41] .The strategy for identifying patients at high risk for cardiovascular complications and cardiovascular mortality should encompass determina-tion of serum cardiac troponins, electrocardiographic markers, such as length of QTc interval and QTc-interval dispersion, and echocardiographic markers (LVMi) 35,[40][41][42][43] .
Early detection of high-risk patients enables timely implementation of adequate therapeutic strategy.The primary therapeutic strategy for lowering cardiovascular mortality rate in patients on HD should include: antiaggregation therapy, control of lipid metabolism disorders and hypertension, while secondary therapeutic strategy includes coronary revascularisation and controle of heart rhythm disorders [44][45][46][47][48] .

Conclusion
Patients on HD have high risk for cardiovascular morbidity and mortality.Hiperhomocysteinemia, anemia, hypertriglyceridemia and uncontrolled hypertension had the highest prevalence of cardiovascular risk factors among all investigated.Echocardiographic assessment for cardiovascular status in patients on HD identifies those with increased risk of cardiovascular complications, LVH, congestive heart failure, and heart valve calcification.Establishing the most sensitive parameters for identifying patients at risk for cardiovascular complications enables successfull treatment.

Table 1 General patients data
*Single pool modeling fractional clearance of body water of urea (KT/V)

Table 2 Basic patients parameters based on outcome during the two-year follow-up
*low-density lipoproteins; † high-density lipoproteins

Table 6 Echocardiographic assessment of left ventricular (LV) systolic function in patients on regular hemodialysis
*disturbed systolic function

Table 8 Echocardiographic assessment of pericardial effusion in patients on regular hemodialysis
*left ventricular posterior wall; † right ventricular anterior wall

Table 9 Disrrhythmia in patients on regular hemodialysis
Petrović D, Stojimirović B. Vojnosanit Pregl 2008; 65(12): 893-900.cigarette smoking, diabetes and obesity.Nontraditional risk factors encompass a number of hemodynamic and metabolic factors.Hemodynamic factors include anemia, sodium and water retention, and increased shunt blood flow.Metabolic risk factors are hyperhomocysteinemia, oxidative stress, microinflammation and disturbed calcium and phosphate metabolism