PLASMA LEVELS OF BRAIN NATRIURETIC PEPTIDES AND CARDIAC TROPONIN IN HEMODIALYSIS PATIENTS

Patients with End-Stage Renal Disease (ESRD) are at high risk of death as a result of the cardiovascular disease (CVD), which cannot be explained by the conventional risk factors only. Haemodialysis patients frequently have elevated serum concentrations of the cardiac troponins T, specifi c markers of myocardial injury. Plasma levels of brain natriuretic peptide (BNP) are elevated in fl uid volume overload and heart failure, and decreased during dialysis. Currently, LV hypertrophy and LV dysfunction are considered the strongest predictors of cardiovascular mortality in dialysis population, and the synthesis of cardiac natriuretic peptides is high in the presence of alterations in the left ventricular (LV) mass and function. Th e aim of this study was to investigate the factors associated with the increased serum levels of BNP and CTN in haemodialysis patients, and their impact on cardiovascular morbidity. In this cross-sectional study we included  patients with ESRD, without coronary symptoms, who were subjected to regular dialysis treatment three times a week for the duration of four hours. Heart failure was defi ned as an ejection fraction (EF) of < , and dyspnoea associated with either elevated jugular pressure or interstitial oedema evidenced in chest X-ray. All patients were in sinus rhythm at the time of the study. Twenty-fi ve patients were on erythropoietin treatment. Blood samples were taken before and after the dialysis session. Our study included  patients ( males,  females). Th e average age was , years (total range -) divided into two groups: euvolemic and hypervolemic. Th e average dialysis time was ,±, months. All haemodialysis patients had excessively high levels of BNP ,±, ng/cm. Plasma cTnT was found to be increased in , of patients. Patients with hypervolemia had signifi cantly higher cTnT levels (,±,), as compared to the euvolemic patients ,±, p<,. Th e elevated cTnT signifi cantly correlated with the level of BNP (p<,), while average post-dialysis BNP was not signifi cantly lower (,±,; R=,; p-ns.) as compared to the pre-dialysis BNP (,±,; R=; p<,). Th e pre-dialysis cTnT was lower (,±,) as compared to the post-dialysis cTnT (average ,). Euvolemic patients had BMI ,±,, as compared to the hypervolemic patients BMI ,±, (p-n.s.). Increased BNP was not PLASMA LEVELS OF BRAIN NATRIURETIC PEPTIDES AND CARDIAC TROPONIN IN HEMODIALYSIS PATIENTS Halima Resić*, Selma Ajanović, Nihad Kukavica, Fahrudin Mašnić, Aida Ćorić Haemodialysis Clinic, University of Sarajevo Clinics Centre, Bolnička ,   Sarajevo, Bosnia and Herzegovina * Corresponding author


Introduction
Determination of the plasma concentrations of cardiovascular peptides in haemodialysis (HD) patients has potential clinical value in: . Determination of volume status .Assessing and improving cardiovascular stability .Determination of degree of heart failure .Survival prognosis Th e haemodialysis patients frequently have elevated cardiac natriuretic peptide levels.Cardiac troponin (cTnT) is exclusively expressed in cardiomyocytes, and is released into circulation after irreversible damage of cardiac muscle ().Release of cardiac markers in ischemia is infl uenced by diff erent factors, the most important being the compartmentation.Th ere are several other reasons for appearance of cTnT, including myocardial damage due to the increased LV wall tension from hypertrophy, or acute or chronic volume overload, a condition that is frequently found in haemodialysis patients.In some studies, cTnT was associated with left ventricular mass and cardiovascular congestion (,).Possible reasons include impaired cardiac haemodynamics or underlying musculature in uraemia.Increased myocardial dilatation in the state of acute or chronic hyperhydration may lead to secretion of cTnT and BNP, and the dialysis procedure infl uences their levels by haemoconcentration.Patients with renal insuffi ciency have increased BNP, and that is an indicator of coronary artery disease and LVH (,).

Patients
In our study we included patients with ESRD, treated by chronic intermittent haemodialysis for a period longer than  months.The study design was crosssectional, with one year follow-up period.The exclusion criteria were the following: age > years, acute myocardial ischaemia, acute infections, and malignancy.The evaluation entailed the following: demographic data, BMI, blood pressure, haematocrit (HTC), assessment of the hydration status.At the time of the inclusion, blood samples for cTnT , BNP, and HTC were drawn prior to dialysis (after weekend) and after.

Methods
HD patients were treated three times a week with the standard bicarbonate dialyses (Na  mmol/L, HCO- mmol/dm  , K-, mmol/dm  , Ca -, mmol/dm  , Mg-, mmol/dm  ).Blood fl ow rate varied between - cm  /min, and standard dialysate flow was  cm  /min.All HD patients were anuric ( h urine volume <  cm  , while a minority of patients (N-) had  h diuresis > cm  / h.Left ventricular function was assessed by -D and Doppler echocardiography.The thickness of ventricular walls and intraventricular septum, and the diameter of LV, were measured by M-mode echocardiography.Hypervolemia was assessed according to clinical score system which included the following parameters: difference to dry weight >, kg, peripheral oedema, radiological signs of pulmonary congestion in the chest X-ray.

Statistical analysis
Data were expressed as means and standard deviations.Categorical variables were expressed as absolute numbers and percentages.Statistical significance was assumed at values p<,.

Results
Thirty patients with ESRD, treated by haemodialysis, were included in our study.The main demographic and clinical characteristic of the patients included in the study are presented in Table .Hypervolemia was found in  out of  patients.Average pre-dialysis serum levels of BNP was elevated ,±, pg/cm  and post-dialysis level of BNP decreased to ,±, (R=,, p=ns.).
Increased BNP was not related to age (p-ns.)and duration of dialysis, but rather to hypervolemia and LV mass index (p<,) (Table ).
The haematocrit level increased significantly during haemodialysis, , vs. , (p<,).Hypervolemia signs were as follows: dry weight >, kg, clinical signs of hypervolemia (oedema, dyspnoea), and radiological signs of pulmonary congestion.Patients with signs of hypervolemia (n-) had significantly higher cTnT (prior to haemodialysis) in comparison to haemodialysis patients without hypervolemia (, ng/cm  vs. , mg /cm  p<,) and the same results were found for BNP.Twenty-five out of  patients were oligoanuric while  were not.High levels of cTnT and BNP were found in oligoanuric patients.
There was a significant linear correlation between the BNP and LV mass index in pre-dialysis (, BNP; LVMI , g/m  ) (p<,) vs. post-dialysis level BNP -, but there was no correlation between BNP and EF (,) (p=ns).
Echocardiography showed left ventricular hypertrophy in , patients.None of the patients had significant heart valve disease.LV dysfunction was found in  patients, with an average left ventricular ejection fraction of ,±,.Fifteen of patients with LV dysfunction also had right ventricular enlargement.

Discussion
Cardiac troponin is released from cardiomyocytes into circulation after irreversible damage of cardiac muscle.High levels of troponin may be caused not only by major coronary artery stenosis, but also by microvascular lesions, silent plaque, rupture or subclinical myocardial fibrosis and necrosis (, ).The reason for cTnT elevation in haemodialysis patients is undetermined.Possible reasons include periodical hemodynamics or underlying cardiac disease with specifi c alterations of cardiac musculature in uraemia (, , ).Th e dialysis membrane may also alter cTnT and BNP concentrations.In our study we found an upper limit of cTnT levels in  hypervolemic patients out of the total of  patients examined.In previous studies, cTnT was associated with left ventricular mass and cardiovascular congestion in chronic haemodialysis patients (, ).Different studies have reported - frequency of cTnT upper limit ().Our study showed that the period of dialysis treatment and patients' age were not associated with high cTnT.Another study showed that age, duration of dialysis, and initial kidney disease, were associated with high cTnT (, ).Actually, little is known about the route of degradation of cTnT; furthermore, the kinetics of decreases and the catabolic path- In our study, serum concentrations of cTnT were signifi cantly higher in oligoanuric patients than in patients with diuresis.Willging et al. () reported rates of urinary clearance of less than , cm  /min. in patients without renal impairment following acute myocardial infarctus.
In chronic renal failure patients, before haemodialysis, there was a positive correlation between serum concentrations of creatinine and cTnT ().In the Lowebeer et al. study a negative correlation between the serum levels of cTnT and creatinine was found in haemodialysis patients ().Th e cardiovascular status in older patients with decreased muscle proved to be worse.
In the early  a research was conducted into the application of cardiac natriuretic peptides for the diagnosis of LVH and systolic dysfunction.High plasma level of BNP in dialysis patients is multifactorial and depends on extra cellular volume expansion.Nita et al. reported that BNP may be a possible indicator of reduced ventricular function in HD patients ().
Different studies reported that plasma BNP has high specifi city and sensitivity in diagnosis of left ventricular dysfunction in patients with normal renal function (, ).Determination of BNP in diagnosing ventricular dysfunction in patients with end stage renal failure has not been thoroughly explored.In our study we found that the brain natriuretic peptide was, to a high degree, correlated with several echocardiographic parameters, including LV mass index and thickness of the left ventricular walls, especially in hypervolemic patients.BNP was elevated in all haemodialysis patients, but significant elevation was found in hypervolemic patients.Possible explanation for high increase of BNP in this group of patients could be that the left ventricular hypertrophy is potentially important cause of elevated natriuretic peptides in dialysis patients.
Our data suggest a signifi cant impact of declining residual diuresis on the level of BNP.Numerous studies showed that measurements of BNP could be helpful for identification of the LVH and left ventricular dysfunction ().

Conclusion
Th is study shows that BNP was  times higher in our dialysis patients.Determining plasma levels of BNP is useful in diagnosing the impaired left ventricular function in HD patients.Continued high plasma level of BNP may indicate the need for further pharmacological treatment with ACE inhibitors in the application of extended or daily haemodialysis.Th e magnitude of cTnT was particularly apparent in patients with fl uid overload.We confi rmed that plasma cTnT is elevated in about  of asymptomatic haemodialysis patients.

TABLE 1 .
Characteristics of patientsAverage age of patients was ,±, years and average period of dialysis treatment was ,±, months.Th e primary renal diseases were nephroangiosclerosis (), glomerulonephritis , polycistic kidney disease , pyelonephritis , and diabetic nephropathy .