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Echocardiography in patients with chronic kidney diseases
CRVASA-540; No. of Pages 9 cor et vasa xxx (2017) e1–e9
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Review article
Echocardiography in patients with chronic kidney diseases§,§§ Jan Malík *, Vilém Danzig, Vladimíra Bednářová, Zdenka Hrušková Department of Cardionephrology, Complex Cardiovascular Center, General University Hospital, First Faculty of Medicine, Charles University, Karlovo náměstí 32, Praha 2 128 08, Czechia
article info
abstract
Article history:
Vast majority of chronic kidney disease patients die from cardiovascular complications.
Received 23 June 2017
Echocardiography is a fundamental method, which reveals many of them. They include
Accepted 29 July 2017
especially dilatation and systolic dysfunction of the left ventricle and atrium, left ventricular
Available online xxx
hypertrophy, diastolic dysfunction of the left ventricle, heart calcification, which could lead
Keywords:
pulmonary hypertension. Patients with chronic kidney failure differ from the general
Echocardiography
population by cyclic changes of hydration and by the presence of a low resistant arteriove-
Chronic kidney disease
nous shunt (hemodialysis access). These factors significantly affect the actual echocardio-
Heart failure
graphic finding.
up to the development of stenotic valvular disease, right ventricular dysfunction and
Pulmonary hypertension
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mortality of CKD patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodynamic fluctuations, adequate dry weight setting . . . . . . . . . . . . . . . . . . Lack of guidelines, recent attempt of unification . . . . . . . . . . . . . . . . . . . . . . . . Left ventricular hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Left ventricular dilatation and impaired contractility . . . . . . . . . . . . . . . . . . . . . Left ventricular diastolic dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Left atrial dilatation and dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Right ventricular dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extraosseal calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Valvular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pericardial diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The effect of a single hemodialysis session on echocardiographic parameters . The effect of arteriovenous access flow volume . . . . . . . . . . . . . . . . . . . . . . . . .
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This study was supported by the grant of the Agency of Health Research of the Czech Republic 17-31796A. Echocardiography device was obtained thanks to the European fund for regional development CZ.2.16/3.1.00/24012. * Corresponding author. E-mail addresses: [email protected] (J. Malík), [email protected] (V. Danzig), [email protected] (V. Bednářová), zdenka. [email protected] (Z. Hrušková). http://dx.doi.org/10.1016/j.crvasa.2017.07.008 0010-8650/© 2017 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
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Please cite this article in press as: J. Malík et al., Echocardiography in patients with chronic kidney diseases, Cor et Vasa (2017), http://dx. doi.org/10.1016/j.crvasa.2017.07.008
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Conclusions, what should the examination report contain Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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to the hydration status. These factors lead to considerable variability of the parameters measured during echocardiography as we will show below. The diagnosis of heart failure is difficult to establish in ESRD patients, because the heart failure symptoms cannot be easily distinguished from the symptoms of pure hyperhydration. Echocardiography also plays a role in the adequate estimation of the dry weight – especially by the diameter and collapsibility of the inferior vena cava (Table 2). Other signs of elevated central venous pressure include the right atrial dilatation, leftward shift of the atrial septum, tricuspid valve E/e0 ratio higher than 6 and predominance of the systolic flow in the superior vena cava and/or in the hepatic veins.
Introduction Chronic kidney disease (CKD) is defined according to KDIGO (Kidney Disease Improving Global Outcomes) 2012 guidelines as a functional or structural kidney abnormity, lasting for at least 3 months. CKD could be classified according to etiology, glomerular filtration rate and/or albuminuria [1] – see Table 1. According to epidemiological data, CKD G3-G5 affects approximately 10% of adult population. Therefore, it is a state with serious medical, social and economic consequences. The most frequent CKD causes include especially type 2 diabetes mellitus, vascular disease (hypertension and renal artery disease), primary and secondary glomerulopathy or polycystic kidney disease in the Western countries.
Lack of guidelines, recent attempt of unification
Mortality of CKD patients
It is probably the high variability of echocardiographic findings, which is responsible for the fact that up to now there are no official guidelines of the European Society of Cardiology or of its American counterparts for the echocardiographic examination of patients with CKD. The cardiologists' knowledge of CKD patients specifics of is usually inadequate and the cardiac complications are mostly managed by the nephrologists. This is probably why different cut-off values not respecting the current echocardiographic Guidelines were used. Recently established ‘‘Acute Dialysis Quality Initiative XI workgroup’’ suggested therefore a new classification of heart failure in ESRD patients. It is based on the presence of 3 criteria: (1) echocardiografic evidence of structural heart disease; (2) shortness of breath, which cannot be explained by pulmonary disease; (3) improvement of congestion symptoms by ultrafiltration [3]. The same group chose the following 8 echocardiographic signs of the structural heart disease [4] – the latter is present in case of positive finding of at least one criterion – see Table 3. Despite it is a positive attempt to the standardization of the structural heart disease in ESRD patients, we have the following objections: (1) most importantly, pulmonary
CKD increases cardiovascular morbidity and mortality even in the milder stages. In end-stage renal disease (ESRD) patients, the mortality is approximately 10 times higher than in agematched controls. [2]. Cardiovascular diseases account for almost 50% of deaths. The understanding of the cardiovascular disease etiopathogenesis is a mandatory step in the attempt to lower ESRD mortality. Echocardiography has a pivotal role – similarly to other cardiological diseases.
Hemodynamic fluctuations, adequate dry weight setting Dramatic changes of hydration occur especially in anuric patients – continuous water retention is followed by the fast fluid loss by ultrafiltration during hemodialysis. ESRD patients suffer usually from arterial hypertension with the need of pressure-lowering medication – both blood pressure itself and the effect of antihypertensive medication changes according
Table 1 – Chronic kidney disease classification [1]. CKD level according to GFR Level G1 G2 G3a G3b G4 G5
CKD level according to albuminuria
GFR (ml/min/1.73 m2)
Level
≥90 60–89 45–59 30–44 15–29 <15
A1
<30
<3
A2
30–300
3–30
A3
>300
>30
Albuminuria (mg/24 h)
Albumin/creatinine ratio in urine (mg/mmol)
GFR = glomerular filtration rate. G1 and G2 categories do not fulfill CKD criteria in the lack of renal damage evidence.
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Table 2 – Central venous pressure estimation according to the inferior vena cava diameter and collapsibility. Diameter (mm)
Collapsibility
Central venous pressure (mmHg)
<15 mm 15–25 15–25 >25 >25
Total collapse >50% <50% <50% No change
0–5 6–10 11–15 16–20 >25
Patient in supine position (458), diameter measurement should be done at the end of exspirium after a deep inspirium. Some authors prefer sniffing– short strenuous nose inspirium. We present one of the used variants, which is objected by some echocardiographers. Inferior vena cava dilatation could also be a result of significant tricuspid valve regurgitation, more developed Eustach's valve in the right atrium, left-to-right intracardial shunts, athletic heart, but also mechanical ventilation especially when using higher values of the positive end-expiratory pressure; in the latter case, vein collapse occurs during the inspiratory phase.
Table 3 – Structural heart disease criteria according to the Acute Dialysis Quality Initiative XI workgroup and cutoff values by the European and American guidelines. Parameter Left ventricular hypertrophy Higher left ventricular volume Left ventricular systolic dysfunction or finding of regional wall motion abnormality Diastolic dysfunction Left atrial dilatation Right ventricular dilatation
Acute Dialysis Quality Initiative XI workgroup criteria [4]
European and American echocardiography societies criteria
,LVMi > 110 g/m2, < > 130 g/m2 nebo ,LVMI > 47 g/m2.7, < > 50 g/m2.7 LVEDVi > 86 ml/m2 LVESVi > 37 ml/m 2 EF ≤ 45%
,LVMi > 95 g/m2, < > 115 g/m 2
≥grade 2 LAVi > 34 ml/m 2 Not stated
≥grade 1 LAVi > 34 ml/m 2 Basal cross section >41 mm Indexoved EDA, > 11.5 cm2/m2, < > 12.6 cm2/ m2 TAPSE < 17 mm FAC < 35% Systolic velocity of the lateral tricuspid annulus (s0 ) < 9.5 cm/s RIMP (right ventricular Tei index) >0.43 when using pulsed Doppler imaging or >0.54 when using tissue Doppler imaging Peak velocity of the tricuspid regurgitation > 2.9–3.4 m/s +/ further echo signs of pulmonary hypertension Various scores in the literature, but not in guidelines – see the paragraph Moderate to significant stenosis/regurgitation
Right ventricular systolic dysfunction
Systolic velocity of the lateral tricuspid annulus (s0 ) <9.5 cm/s or semiquantitatively abnormal systolic function
Pulmonary hypertension
Not stated
Calcification score
Not stated
Mitral or aortic valve disease
Moderate to significant stenosis/ regurgitation
hypertension is not mentioned; (2) cardiac calcification is not mentioned; (3) the cutoff values do not correspond to the current echocardiographic guidelines – see Table 3. Let us look at the particular echocardiographical pathologies of ESRD patients in more detail.
Left ventricular hypertrophy Left ventricular hypertrophy (LVH) develops already during the milder CKD stage – it affects up to 20% of CKD 1–3 patients [5]. During further progression of CKD left ventricular mass also increases and LVH affects up to 80% of ESRD patients during hemodialysis therapy initiation [6]. Successful kidney transplantation leads to LVH regression and even to the normalization of the global longitudinal peak strain [7].
LVEDVi > 74 ml/m2 LVESVi > 31 ml/m 2 EF < 52%
Etiopathogenesis: cyclic water overload lead to left ventricular volume overload in ESRD patients, which is the most important mechanism of eccentric LVH development. Simultaneously, arterial hypertension, which could have nephrogenic and/or renovascular origin, is a factor leading to the concentric LVH. The affection of aorta and of arteries by the accelerated atherosclerosis and medial calcinosis is responsible for higher wall stiffness, which is usually quantified by the increased pulse wave velocity [8]. Lower aortic compliance leads to the reduction of the aortic capacitance function. Increased pulse wave velocity leads to the faster return of the reflected wave – when the aortic valve is still open – therefore, the left ventricular afterload is increased. Higher pulse pressure (the difference of the systolic and diastolic pressure values) could notify us about this problem. Specific mechanisms of LVH development occur in the storage diseases, such
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as in Anderson-Fabry disease [9]. At the cellular level, LVH is characterized by the myocyte hypertrophy, increased apoptosis, interstitial fibrosis and capillary rarefaction. Blood pressure decrease during hemodialysis leads to the sympathetic activation, but also to the repeated myocardial ischemia especially in the areas of more pronounced capillary rarefaction. This is one of the factors leading to fibrotization. According to the recent research, increased local production of steroids, angiotensin and fibroblast growth factor (FGF)-23 represent the biochemical mechanisms responsible for LVH fibrotization [10,11]. Echographic criteria: according to the common Guidelines of the American Society of Echocardiography and of the European Association for Cardiovascular Imaging (ASE/EACI) [12] the left ventricular mass could be calculated using both Mmode and B-mode, keeping in mind that the B-mode values are lower. Upper-normal left ventricular mass is in case of Mmode 95 g/m2 in females and 115 g/m2 in males. This cutoff value is mentioned also in the Czech summary of the Guidelines for the Diagnostics and Therapy of Hypertension [13]. Concentric and eccentric LVH and concentric remodeling should be distinguished according to the relative wall thickness. Prognostic values: the association between LVH and total mortality has been described by Foley et al. already in 1995: in patients with non-dilated left ventricle, the presence of LVH was linked to 3.39 death hazard ratio, in patients with both dilated and hypertrophic left ventricle this hazard ratio was as high as 17 [2]. Hemodialysis technique and medication have changed since those times. In a more recent study of 445 patients, the diagnosis of LVH brought increased risk of combined end-point (all-cause mortality and progression of CKD to ESRD) the increase of relative risk to 2.33 in case of concentric hypertrophy and to 2.30 in case of eccentric hypertrophy [14]. Eccentric hypertrophy led to higher number of cardiovascular events that the concentric LVH. In another study [15] the presence of LVH was connected with higher occurrence of sudden cardiac death. Concentric remodeling is a frequent finding in ESRD studies using cardiac magnetic resonance and it was associated with increased left ventricular dyssynchrony measured by time to peak strain dispersion [16].
Left ventricular dilatation and impaired contractility This category includes global hypokinesis and also segmental contractility impairment similar to the general population. Etiopathogenesis of the left ventricular diffuse hypokinesis and dilatation includes mechanisms known from the general population (especially coronary artery disease and arterial hypertension-both these diseases are very frequent in ESRD patients) and also mechanisms typical for ESRD itself. The latter group includes hyperhydration, (dilatation and hypokinesis is reversible in this case), consequences of long-term hyperkinetic circulation (anemia, high dialysis access flow volume). In extreme cases, hyperkinetic heart failure develops. Fortunately, the dilatation and dysfunction due to hyperkinetic circulation are usually reversible – after correction of anemia or flow-reducing surgery of the dialysis access.
Regional wall motion abnormalities (RWMA) develop as a result of coronary artery disease – similarly to the general population. Moreover, RWMAs develop in some patients during hemodialysis and last for several hours after it. Physiologically, regional left ventricular stunning explains these intradialytic RWMAs. One study [17] explains the development of intradialytic RWMAs by the global myocardial hypoperfusion during hemodialysis, which occurs even in patients without significant stenosis on coronary angiography. The same group has shown that in patients with known repeated dialysis induced RWMAs, the left ventricular ejection fraction decreases by 10% within one year [18]. RWMAs developed more frequently in patients suffering from intradialytic hypotension. The latter could be a result of inadequate (too low) estimation of patient's dry weight, of impaired autoregulatory mechanisms due to autonomic dysfunction, but also due to excessive heating of the dialysis solution: Jefferies et al. showed that individualized setting of dialysis solution temperature (mean 36.0 8C) in comparison to automatic setting to 37.0 8C led to a significant reduction of RWMAs – authors suggested that the lower temperature prevents systemic vasodilatation with subsequent hypotension [19]. Echocardiographic criteria: according to the common European-American Guidelines, the normal end-diastolic left ventricular diameter is 42.0–58.4 mm in males and 37.8– 52.2 mm in females, normal end—diastolic volume (LVEDV) calculated by the modified Simpson method and indexed to body surface area is 34–74 ml/m2 in males and 29–61 ml/m2 in females [20]. These values were derived from the healthy population. Hickson et al. [4] used the upper value of normal LVEDV 86 ml/m2 or systolic volume above 37 ml/m2. Other studies used different cutoff values. The problem in ESRD patients is significant LVEDV dependency on the actual hydration, in other words in the time delay since the previous hemodialysis. According to our opinion, this time delay should be at least 24 h, if the increased central venous pressure is not assessed by inferior vena cava (Table 2). Ejection fraction quantification should be performed by planimetry according to the guidelines [12], RWMAs – if present – should be described by the segmental analysis of contractility. Some authors use special wall motion score. Dialysis-induced RWMAs could be distinguished from other RWMAs due to coronary artery disease by another echocardiography with longer time delay since the previous hemodialysis. Prognostic impact: left ventricular dilatation was linked to poorer prognosis only in some studies. Clear increase of mortality is linked to left ventricular systolic dysfunction. The highest mortality affects patients with the systolic dysfunction of both ventricles [4]. Patients with dialysis induced RWMA are at risk of faster systolic function decline [18]. From the practical point of view, we recommend coronary angiography in case of the first RWMA occurrence with possible revascularization.
Left ventricular diastolic dysfunction The term ‘‘diastolic dysfunction’’ includes the issues of both left ventricular relaxation and compliance and also increased filling pressures.
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Etiopathogenesis: frequent LVH brings conditions for the development of diastolic dysfunction in ESRD patients. The filling pressures are also significantly influenced by hydration and thus change with the phase of hemodialysis therapy. Echocardiographic criteria: according to the current Guidelines, the evaluation of left ventricular diastolic dysfunction should be based primarily on the E/A ratio of transmitral flow, on tissue Doppler examination of the mitral annulus, on left atrial volume and on the gradient of tricuspid regurgitation [21]. The former combination of criteria is the stumbling block of diastolic function estimation in hemodialyzed patients: (1) the height of E wave is mainly influenced by the actual hydration (left ventricular preload); (2) the movement of the lateral part of mitral annulus is frequently limited by the present calcification and less data is available for the septal part; (3) left atrial dilatation is very frequent in ESRD patients especially due to (cyclic) overhydration; (4) pulmonary hypertension is also very frequent, but because of other mechanisms explained below. Besides these parameters, the presence of LVH should be also taken into account. Diastolic dysfunction was observed in up to 50% of hemodialyzed patients. Pragmatically, we frequently assume that the diastolic dysfunction is present and we attempt at least to estimate the filling pressures. They are without any doubt increased in restrictive type of transmitral flow, in high values of E/e0 ratio above 14. The actual estimation of central venous pressure should be taken into account. Prognostic impact: long-term increase of the filling pressures increases both the number of cardiovascular complications and mortality [22].
Left atrial dilatation and dysfunction Left atrium is the most frequently dilated cardiac cavity. Etiopathogenesis: the left atrial wall is very thin; therefore the left atrium is prone to volume induced changes – especially to cyclic hyperhydration in chronically hemodialyzed patients. Other mechanisms of left atrial dilatation include the left ventricular diastolic dysfunction, less frequently also disease of the aortic and mitral valves. Functionally, the left atrium plays 3 functions: (1) pump function, which contributes to the left ventricular filling at the late diastole; (2) reservoir functioncollection of the blood, which continuously flows from the pulmonary veins; (3) conduit function in the early diastolic phase. Left atrial dilatation and dysfunction lead to atrial fibrillation, which leads to further dilatation. Echocardiographic criteria: the cross-sectional left atrial diameter was measured in the parasternal view, then the atrial length and width in the apical 4 chamber view. Nowadays, planimetric calculation of the left atrial volume is preferred and indexed to body surface area (upper normal value is 34 ml/m2. Alternatively, 3D examination of the left atrial volume is used, but this method is prone to good visualization. Left atrial ejection fraction could be calculated by planimetry similarly to the left ventricular ejection fraction. Prognostic impact: some studies have shown higher cardiovascular morbidity of ESRD patients with dilated left atrium [23]. Left atrial ejection fraction decreases together with age and longer dialysis vintage [24].
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Right ventricular dysfunction Etiopathogenesis: right ventricular dysfunction is usually the result of pulmonary hypertension. Other factors include cyclic overhydration, higher dialysis arteriovenous access flow, coronary artery disease and, less frequently, primary disease of the right heart valves. Right ventricular dysfunction could negatively influence the function of the left ventricle by the mechanism of interdependence (especially the left ventricular filling is impaired). Echocardiographic criteria: the cross-sectional right ventricular diameter in the parasternal long axis view was traditionally used for the assessment of its size. However, this parameter is the most variable, which comes from the foolish attempt to measure the cross section of a triangle (the right ventricle has almost this shape in this view). The most accurate assessment of the right ventricle size in comparison to cardiac magnetic resonance is the calculation of area in the apical 4 chamber diastolic view. Other used parameters include cross-sectional basal diameter at the level of tricuspid valve annulus and in the mid-length of the right ventricle – see Fig. 1. Performed trials in ESRD patients used only some parameters of right ventricular systolic function – especially TAPSE (tricuspid annular plane systolic excursion) and systolic velocity of tricuspid annulus in tissue Doppler examinations. This selection is logical – although the right ventricle has 3 muscle layers (longitudinal, radial and spiral), longitudinal shortening plays the most important role. European and American guidelines recommend also the use of the right ventricle myocardial performance index (RIMP – right ventricle index of myocardial performance, also called Tei index). The latter includes both systolic and diastolic time interval (isovolumic contraction time + ejection time + isovolumic relaxation time – see Fig. 2. Another parameter mentioned by the guidelines [20] is the fractional right ventricle area change (FAC), which could be calculated similarly to ejection fraction after getting enddiastolic area (EDA) and end-systolic area (ESA) from apical 4-chamber view, resp. from the modified view concentrated
Fig. 1 – Most frequently used parameter of right ventricle size. Apical 4 chamber view: measurement of enddiastolic area (EDA), basal diameter (at the level of tricuspid annulus) and mid-diameter is depicted.
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Fig. 2 – Tei index of the right ventricle. RIMP (right ventricle index of myocardial performance) called also Tei index of the right ventricle – usage of the tissue Doppler assessment of the lateral part of the tricuspid annulus. It is used according to the following equation: RIMP = (IVRT + IVCT)/ET = (TCO-ET)/ET. Abbreviations: IVRT, isovolumic relaxation time; IVCT, isovolumic contrationtime; TCO, tricuspid valve closure to opening time; ET, ejection time. The inclusion of the systolic phase (isovolumic contraction and ejection duration) and diastolic phase (duration of isovolumic relaxation, which is one of the diastolic function descriptors), means that Tei index assess right ventricular performance globally. However, it is unreliable when the right atrial pressure is increased [20].
on the largest part of the right ventricle. On the contrary, calculation of right ventricular volume and ejection fraction is difficult by 2D echocardiography, because the right ventricle has a complex shape similar to a pyramid. First data about the ejection fraction calculation by 3D echocardiography are available. Global longitudinal right ventricular strain is also used – some authors calculate it only from the free wall, others include also the interventricular septum [12]. If the latter method is used, the obtained value is lower (resp. less negative). Details of the correct assessment of the size and function of right-sided heart structures are explained in the recent book [25] (in Czech language), or in the guidelines [20]. Prognostic impact: right ventricular dysfunction is linked to increased mortality of ESRD patients [4], even higher risk brings the dysfunction of both ventricles.
Pulmonary hypertension Etiopathogenesis: pulmonary hypertension is defined as the increase of pulmonary artery mean pressure above 25 mmHg. It affects up to 50% of ESRD patients [26]. Many mechanisms have been described: the influence of uremic toxins on the pulmonary arteries (increased oxidation stress, endothelial dysfunction, vitamin D deficit, etc.), left-sided heart disease, cyclic overload, hyperkinetic circulation as a result of anemia and of dialysis arteriovenous access, thromboembolism
(including thrombi released during thrombolysis of the dialysis access), sleep apnoea syndrome and others. Echocardiographic criteria: thanks to it non-invasiveness, echocardiography plays a fundamental role in the pulmonary hypertension diagnosis, despite this method possess some pitfalls [25]. Morphological signs of pulmonary hypertension include right ventricular and atrial dilatation, dilatation of the common pulmonary trunk (seen in the parasternal short axis view) above 25–30 mm, interventricular septal flattening (continuous left ventricular D-shape is the extreme), and inferior vena cava dilatation. Functional signs include the pulmonary artery acceleration time shortening below 100 ms or dicrotic notch in its deceleration phase (so called type III flow), the presence of regurgitation on right-sided valves. The estimation of the actual pressure in the pulmonary artery is usually derived from the peak gradient of the tricuspid regurgitation. The estimated value of the central venous pressure should be added to the peak gradient (see Table 2) to get the systolic right ventricular pressure (which is equal to the systolic pulmonary artery pressure) supposing that the pulmonary valve stenosis is excluded. From the practical point of view, it should be stressed out that only high quality regurgitation wave from the spectral Doppler should be used for analysis. Another problem brings severe tricuspid regurgitation – in this case there is fast equalization of the ventricular and atrial pressures – therefore, the measured peak gradient underestimates the actual systolic pressure. Analogically, the systolic pulmonary artery pressure (PASP) can be derived from the maximal gradient of pulmonary regurgitation and the minimal gradient for the estimation of the diastolic pulmonary artery pressure (PADP). Some authors use more complicated approach for the estimation of the mean pulmonary pressure (MAP), such as MAP = PASP/3 + 2PADP/3. Prognostic impact: the presence of pulmonary hypertension increases considerably and significantly all-cause mortality of CKD (including ESRD) patients.
Extraosseal calcification Extraosseal calcification affects many organs, including heart and arteries. Etiopathogenesis: vascular calcification appears already in CHD stage 3. Pro-calcification factors include high levels of calcium, high levels of phosphates, hyperparathyreosis and FGF-23. On the contrary, there are protecting factors, such as fetuin and vitamin K-dependent GLA protein – the risk of calcifications is therefore increased by the warfarin therapy (warfarin is a vitamin K antagonist). The calcification of intima and media is an irreversible active process similar to bone formation – phenotype transformation of myocytes to osteoblast-like cells develops. Calcification of the medial wall layer (mediocalcinosis) leads to increased arterial wall rigidity and lumen narrowing. As a result, organ ischemia develops. In extreme cases, the calcification spread to the cardiac valves with the development of stenotic valvular disease (especially of aortic and mitral valves). Interestingly, there are some common mechanisms of myocardial calcification and of LVHFGF-23 is involved in both states. This factor is produced by osteocytes and physiologically it increases renal phosphate
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Fig. 3 – Advanced heart calcification. Parasternal liongaxis view. There is advanced calcification of mitral annulus, leaflets and of chordae tendineae, of aortic annuls and leaflets and of the septal endocardium of the left ventricle. This patient suffered from severe aortic and mitral stenoses, both valves have been successfully replaced.
excretion – however, renal phosphate excretion decreases with the progression of CKD. The rise of FGF-23 levels precedes the rise of parathormone and both these molecules play a role in the development of extraosseous calcifications. Increased FGF-23 level is also a predictor of cardiovascular complications. Besides its effect on the development of calcifications, FGF-23 possess many other unfavorable effects – it increases production of inflammatory cytokines, accelerates both the development of CKD and of LVH, affect immune mechanisms, damages endothelium [27]. Echocardiographic criteria and prognostic impact: a number of heart calcification schemes have been developed to describe the calcification load. The simplest ones differentiate 3–4 stages and calculate calcifications of the mitral annulus, mitral valve leaflets and both annulus and cusps of the aortic valve. The most detailed is the recently developed ‘‘Global calcification score’’ with the maximum of 12 points: up to 3 points for the affection of the mitral annulus (each third 1 point), posterior leaflet movement restriction (1 point), leaflet calcification (0–2 points), calcification of the subvalvular apparatus (1 point), of aortic valve cusps (up to 3 points) and affection of the aortic valve annulus (1 point). A recent study revealed almost linear relation between heart calcification score and total mortality + risk of ischemic stroke [28]. Calcification could affect heart valves (Fig. 3). It is necessary to highlight higher sensitivity and preciseness of computerized tomography in the assessment of cardiac calcifications.
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Fig. 4 – Arteriovenous dialysis access flow volume calculation by ultrasonography. The calculation should be performed in the brachial artery in case of native arteriovenous fistulas and in the graft (far from arterial anastomosis) in case of arteriovenous grafts (this case). Vascular diameter and time-averaged mean velocity (TAMEAN – green curve) is measured. The calculation is based on the following equation: Q = pr2 T TAMEAN, where Q = flow volume, r = radius. This equation is a part of many ultrasound devices, but frequently as an option. For the manual calculation, we should use the radius in centimeters, velocity in cm/s and magnify the result by 60. Then we get flow volume in ml/min.
stenosis development is accelerated in CKD patients, which is also true for biological heart valves. Echocardiographic criteria: the same criteria as in the common population are used. It is important not to rely on the pressure gradients of stenotic valves: hyperkinetic circulation is frequent in ESRD patients especially due to arteriovenous dialysis access – therefore, the pressure gradients overestimate the hemodynamic impact. Calculations based on continuity equation should be preferred.
Pericardial diseases Pericardial effusion was a frequent finding in ESRD patients in 1970s. Thanks to the improvements in hemodialysis therapy it is now rare and occurs only in patients coming ‘‘from the street’’ and in some subjects suffering from a systemic disease, such as lupus erythematosus, etc. Some studies observed pericardial thickening in ESRD patients. Nevertheless, computerized tomography is more precise in this aspect [29]. Such thickening could influence ventricular filling and resulting constrictive pericarditis was also described [30].
Valvular disease Etiopathogenesis: valvular disease develops in CKD patients thanks to similar mechanisms that occur in general population. Regurgitation of atrioventricular valves is more frequent due to volume overload. Degeneration of the valves and
The effect of a single hemodialysis session on echocardiographic parameters Hemodialysis alters fast and considerably milieu interieur, especially in anuric patients, it decreases body water volume
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and, therefore, also blood pressure. These mechanisms are mirrored by the changes of echocardiographic parameters, as could be observed if we perform 2 examinations: before and after hemodialysis. In the vast majority of patients, the fall of water volume and blood pressure leads to the decrease of atrial and ventricular volumes, of the filling pressures, of the regurgitant valve disease severity. Cardiac output and pulmonary artery pressure also decrease [24,31]. Some patients develop already mentioned RWMAs during hemodialysis. Similarly, arteriovenous access flow volume is also lower. However, some 5–10% of patients react ‘‘paradoxically’’: their cardiac output increases as well as the pulmonary artery pressure and arteriovenous access flow. It is typical for patients with water overload-usually unable to follow fluid intake restrictions, when the heart autoregulatory mechanisms are exhausted. Left ventricular unloading during hemodialysis probably plays a role in the increase of cardiac output and related parameters, but the exact mechanisms are not yet described in detail. We also observe worsening of mitral regurgitation in some patients after hemodialysis. It is probably due to intradialytic RWMA, leading to mechanisms similar to ischemic mitral regurgitation. So when should be echocardiography performed in hemodialysis patients? Ideally at least 24 h after the previous hemodialysis when we can already expect equilibrium between intravascular and extravascular hydration. From the practical point of view, it is important also because the echographic visibility is worse shortly after hemodialysis.
The effect of arteriovenous access flow volume Functioning vascular access is necessary for hemodialysis. Performed studies confirmed that the best option is the native arteriovenous shunt (‘‘fistula’’) – patients with this type of access suffer from significantly less complications and have longer life expectancy than patients with arteriovenous (polytetrafluoroethylene) graft or dialysis catheter. Flow volume 500–1500 ml/min is considered ‘‘normal’’ or ‘‘usual’’ (they represent 10–30% of resting cardiac output!). However, not exceptionally, the flow volume reaches 2–5 l/min! Subsequent complications are therefore not surprising for cardiologists [32]. After the creation of arteriovenous access, blood pressure decreases and levels of B-natriuretic peptide increase, the volume of heart cavities is larger, left ventricular diastolic function worsens as well as the severity of regurgitant valve disease. Some patients with high-flow access hand ischemia and/or hyperkinetic heart failure develops. The increase of cardiac output secondary to high access flow leads to the increase of pulmonary artery pressure. According to our experience, the majority of ESRD patients referred to our Cardiocenter for pulmonary hypertension, had high-flow access. After the surgical flow correction the estimated pulmonary systolic pressure decreased by 10–40 mmHg (own unpublished data). Vascular access flow volume also contributes to the decompensation of classic congestive heart failure, but the effect is very individual. Vascular access flow volume could be measured using dilution techniques at the hemodialysis units or with the use
of linear (‘‘vascular’’) ultrasound probe at the brachial artery – similarly to cardiac output measurement in the left ventricular outflow tract (Fig. 4). Due to all aforementioned reasons, it is desirable for the cardiologist to be aware of arteriovenous access flow volume in the majority of cardiac pathologies – surgical access flow reduction is not only easier than cardiac surgery, but in many patients it is the causal therapy. On the other hand, it should be mentioned that many patients tolerate high access flow very well. This is why the asymptomatic high access flow is left without intervention and in many countries it is even not an indication to echocardiography. According to our opinion, such patients should be examined by echocardiography every 6–12 months and in case of ventricular dilatation/dysfunction or pulmonary hypertension development, the patient should be indicated to flow reducing surgery.
Conclusions, what should the examination report contain The main feature of echocardiographical examinations of ESRD patients treated by hemodialysis is the dependency of many parameters on actual hydration and sometimes also on arteriovenous access flow volume. These include diameters/ volumes of cardiac cavities, filling pressures, estimated pulmonary artery pressure, severity of valvular disease. Appropriate setting of dry weight is complicated and according to our experience it is sometimes over- or underestimated even by kilograms (liters of water). Therefore, the necessary requirement for the echocardiographer examining CKD/ESRD patients is the estimation of actual hydration (central venous pressure), time delay since the previous hemodialysis (>24 h advisable) and the presence or absence cardiac calcifications should be also mentioned. We recommend also the quantification of vascular access flow volume especially if it is not measured at the hemodialysis units. Close cooperation of nephrologists and cardiologists is beneficiary for the patients. An example of such cooperation is the Cardionephrology department of the Complex Cardiovascular Center, General University Hospital, Prague, where the patients are examined simultaneously by a cardiologist and by a nephrologist.
Conflict of interest None declared.
Ethical statement Authors state that the research was conducted according to ethical standards.
Funding body None.
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Review article
Echocardiography in patients with chronic kidney diseases§,§§ Jan Malík *, Vilém Danzig, Vladimíra Bednářová, Zdenka Hrušková Department of Cardionephrology, Complex Cardiovascular Center, General University Hospital, First Faculty of Medicine, Charles University, Karlovo náměstí 32, Praha 2 128 08, Czechia
article info
abstract
Article history:
Vast majority of chronic kidney disease patients die from cardiovascular complications.
Received 23 June 2017
Echocardiography is a fundamental method, which reveals many of them. They include
Accepted 29 July 2017
especially dilatation and systolic dysfunction of the left ventricle and atrium, left ventricular
Available online xxx
hypertrophy, diastolic dysfunction of the left ventricle, heart calcification, which could lead
Keywords:
pulmonary hypertension. Patients with chronic kidney failure differ from the general
Echocardiography
population by cyclic changes of hydration and by the presence of a low resistant arteriove-
Chronic kidney disease
nous shunt (hemodialysis access). These factors significantly affect the actual echocardio-
Heart failure
graphic finding.
up to the development of stenotic valvular disease, right ventricular dysfunction and
Pulmonary hypertension
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mortality of CKD patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodynamic fluctuations, adequate dry weight setting . . . . . . . . . . . . . . . . . . Lack of guidelines, recent attempt of unification . . . . . . . . . . . . . . . . . . . . . . . . Left ventricular hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Left ventricular dilatation and impaired contractility . . . . . . . . . . . . . . . . . . . . . Left ventricular diastolic dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Left atrial dilatation and dysfunction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Right ventricular dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pulmonary hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Extraosseal calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Valvular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pericardial diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The effect of a single hemodialysis session on echocardiographic parameters . The effect of arteriovenous access flow volume . . . . . . . . . . . . . . . . . . . . . . . . .
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This study was supported by the grant of the Agency of Health Research of the Czech Republic 17-31796A. Echocardiography device was obtained thanks to the European fund for regional development CZ.2.16/3.1.00/24012. * Corresponding author. E-mail addresses: [email protected] (J. Malík), [email protected] (V. Danzig), [email protected] (V. Bednářová), zdenka. [email protected] (Z. Hrušková). http://dx.doi.org/10.1016/j.crvasa.2017.07.008 0010-8650/© 2017 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
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Conclusions, what should the examination report contain Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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to the hydration status. These factors lead to considerable variability of the parameters measured during echocardiography as we will show below. The diagnosis of heart failure is difficult to establish in ESRD patients, because the heart failure symptoms cannot be easily distinguished from the symptoms of pure hyperhydration. Echocardiography also plays a role in the adequate estimation of the dry weight – especially by the diameter and collapsibility of the inferior vena cava (Table 2). Other signs of elevated central venous pressure include the right atrial dilatation, leftward shift of the atrial septum, tricuspid valve E/e0 ratio higher than 6 and predominance of the systolic flow in the superior vena cava and/or in the hepatic veins.
Introduction Chronic kidney disease (CKD) is defined according to KDIGO (Kidney Disease Improving Global Outcomes) 2012 guidelines as a functional or structural kidney abnormity, lasting for at least 3 months. CKD could be classified according to etiology, glomerular filtration rate and/or albuminuria [1] – see Table 1. According to epidemiological data, CKD G3-G5 affects approximately 10% of adult population. Therefore, it is a state with serious medical, social and economic consequences. The most frequent CKD causes include especially type 2 diabetes mellitus, vascular disease (hypertension and renal artery disease), primary and secondary glomerulopathy or polycystic kidney disease in the Western countries.
Lack of guidelines, recent attempt of unification
Mortality of CKD patients
It is probably the high variability of echocardiographic findings, which is responsible for the fact that up to now there are no official guidelines of the European Society of Cardiology or of its American counterparts for the echocardiographic examination of patients with CKD. The cardiologists' knowledge of CKD patients specifics of is usually inadequate and the cardiac complications are mostly managed by the nephrologists. This is probably why different cut-off values not respecting the current echocardiographic Guidelines were used. Recently established ‘‘Acute Dialysis Quality Initiative XI workgroup’’ suggested therefore a new classification of heart failure in ESRD patients. It is based on the presence of 3 criteria: (1) echocardiografic evidence of structural heart disease; (2) shortness of breath, which cannot be explained by pulmonary disease; (3) improvement of congestion symptoms by ultrafiltration [3]. The same group chose the following 8 echocardiographic signs of the structural heart disease [4] – the latter is present in case of positive finding of at least one criterion – see Table 3. Despite it is a positive attempt to the standardization of the structural heart disease in ESRD patients, we have the following objections: (1) most importantly, pulmonary
CKD increases cardiovascular morbidity and mortality even in the milder stages. In end-stage renal disease (ESRD) patients, the mortality is approximately 10 times higher than in agematched controls. [2]. Cardiovascular diseases account for almost 50% of deaths. The understanding of the cardiovascular disease etiopathogenesis is a mandatory step in the attempt to lower ESRD mortality. Echocardiography has a pivotal role – similarly to other cardiological diseases.
Hemodynamic fluctuations, adequate dry weight setting Dramatic changes of hydration occur especially in anuric patients – continuous water retention is followed by the fast fluid loss by ultrafiltration during hemodialysis. ESRD patients suffer usually from arterial hypertension with the need of pressure-lowering medication – both blood pressure itself and the effect of antihypertensive medication changes according
Table 1 – Chronic kidney disease classification [1]. CKD level according to GFR Level G1 G2 G3a G3b G4 G5
CKD level according to albuminuria
GFR (ml/min/1.73 m2)
Level
≥90 60–89 45–59 30–44 15–29 <15
A1
<30
<3
A2
30–300
3–30
A3
>300
>30
Albuminuria (mg/24 h)
Albumin/creatinine ratio in urine (mg/mmol)
GFR = glomerular filtration rate. G1 and G2 categories do not fulfill CKD criteria in the lack of renal damage evidence.
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Table 2 – Central venous pressure estimation according to the inferior vena cava diameter and collapsibility. Diameter (mm)
Collapsibility
Central venous pressure (mmHg)
<15 mm 15–25 15–25 >25 >25
Total collapse >50% <50% <50% No change
0–5 6–10 11–15 16–20 >25
Patient in supine position (458), diameter measurement should be done at the end of exspirium after a deep inspirium. Some authors prefer sniffing– short strenuous nose inspirium. We present one of the used variants, which is objected by some echocardiographers. Inferior vena cava dilatation could also be a result of significant tricuspid valve regurgitation, more developed Eustach's valve in the right atrium, left-to-right intracardial shunts, athletic heart, but also mechanical ventilation especially when using higher values of the positive end-expiratory pressure; in the latter case, vein collapse occurs during the inspiratory phase.
Table 3 – Structural heart disease criteria according to the Acute Dialysis Quality Initiative XI workgroup and cutoff values by the European and American guidelines. Parameter Left ventricular hypertrophy Higher left ventricular volume Left ventricular systolic dysfunction or finding of regional wall motion abnormality Diastolic dysfunction Left atrial dilatation Right ventricular dilatation
Acute Dialysis Quality Initiative XI workgroup criteria [4]
European and American echocardiography societies criteria
,LVMi > 110 g/m2, < > 130 g/m2 nebo ,LVMI > 47 g/m2.7, < > 50 g/m2.7 LVEDVi > 86 ml/m2 LVESVi > 37 ml/m 2 EF ≤ 45%
,LVMi > 95 g/m2, < > 115 g/m 2
≥grade 2 LAVi > 34 ml/m 2 Not stated
≥grade 1 LAVi > 34 ml/m 2 Basal cross section >41 mm Indexoved EDA, > 11.5 cm2/m2, < > 12.6 cm2/ m2 TAPSE < 17 mm FAC < 35% Systolic velocity of the lateral tricuspid annulus (s0 ) < 9.5 cm/s RIMP (right ventricular Tei index) >0.43 when using pulsed Doppler imaging or >0.54 when using tissue Doppler imaging Peak velocity of the tricuspid regurgitation > 2.9–3.4 m/s +/ further echo signs of pulmonary hypertension Various scores in the literature, but not in guidelines – see the paragraph Moderate to significant stenosis/regurgitation
Right ventricular systolic dysfunction
Systolic velocity of the lateral tricuspid annulus (s0 ) <9.5 cm/s or semiquantitatively abnormal systolic function
Pulmonary hypertension
Not stated
Calcification score
Not stated
Mitral or aortic valve disease
Moderate to significant stenosis/ regurgitation
hypertension is not mentioned; (2) cardiac calcification is not mentioned; (3) the cutoff values do not correspond to the current echocardiographic guidelines – see Table 3. Let us look at the particular echocardiographical pathologies of ESRD patients in more detail.
Left ventricular hypertrophy Left ventricular hypertrophy (LVH) develops already during the milder CKD stage – it affects up to 20% of CKD 1–3 patients [5]. During further progression of CKD left ventricular mass also increases and LVH affects up to 80% of ESRD patients during hemodialysis therapy initiation [6]. Successful kidney transplantation leads to LVH regression and even to the normalization of the global longitudinal peak strain [7].
LVEDVi > 74 ml/m2 LVESVi > 31 ml/m 2 EF < 52%
Etiopathogenesis: cyclic water overload lead to left ventricular volume overload in ESRD patients, which is the most important mechanism of eccentric LVH development. Simultaneously, arterial hypertension, which could have nephrogenic and/or renovascular origin, is a factor leading to the concentric LVH. The affection of aorta and of arteries by the accelerated atherosclerosis and medial calcinosis is responsible for higher wall stiffness, which is usually quantified by the increased pulse wave velocity [8]. Lower aortic compliance leads to the reduction of the aortic capacitance function. Increased pulse wave velocity leads to the faster return of the reflected wave – when the aortic valve is still open – therefore, the left ventricular afterload is increased. Higher pulse pressure (the difference of the systolic and diastolic pressure values) could notify us about this problem. Specific mechanisms of LVH development occur in the storage diseases, such
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as in Anderson-Fabry disease [9]. At the cellular level, LVH is characterized by the myocyte hypertrophy, increased apoptosis, interstitial fibrosis and capillary rarefaction. Blood pressure decrease during hemodialysis leads to the sympathetic activation, but also to the repeated myocardial ischemia especially in the areas of more pronounced capillary rarefaction. This is one of the factors leading to fibrotization. According to the recent research, increased local production of steroids, angiotensin and fibroblast growth factor (FGF)-23 represent the biochemical mechanisms responsible for LVH fibrotization [10,11]. Echographic criteria: according to the common Guidelines of the American Society of Echocardiography and of the European Association for Cardiovascular Imaging (ASE/EACI) [12] the left ventricular mass could be calculated using both Mmode and B-mode, keeping in mind that the B-mode values are lower. Upper-normal left ventricular mass is in case of Mmode 95 g/m2 in females and 115 g/m2 in males. This cutoff value is mentioned also in the Czech summary of the Guidelines for the Diagnostics and Therapy of Hypertension [13]. Concentric and eccentric LVH and concentric remodeling should be distinguished according to the relative wall thickness. Prognostic values: the association between LVH and total mortality has been described by Foley et al. already in 1995: in patients with non-dilated left ventricle, the presence of LVH was linked to 3.39 death hazard ratio, in patients with both dilated and hypertrophic left ventricle this hazard ratio was as high as 17 [2]. Hemodialysis technique and medication have changed since those times. In a more recent study of 445 patients, the diagnosis of LVH brought increased risk of combined end-point (all-cause mortality and progression of CKD to ESRD) the increase of relative risk to 2.33 in case of concentric hypertrophy and to 2.30 in case of eccentric hypertrophy [14]. Eccentric hypertrophy led to higher number of cardiovascular events that the concentric LVH. In another study [15] the presence of LVH was connected with higher occurrence of sudden cardiac death. Concentric remodeling is a frequent finding in ESRD studies using cardiac magnetic resonance and it was associated with increased left ventricular dyssynchrony measured by time to peak strain dispersion [16].
Left ventricular dilatation and impaired contractility This category includes global hypokinesis and also segmental contractility impairment similar to the general population. Etiopathogenesis of the left ventricular diffuse hypokinesis and dilatation includes mechanisms known from the general population (especially coronary artery disease and arterial hypertension-both these diseases are very frequent in ESRD patients) and also mechanisms typical for ESRD itself. The latter group includes hyperhydration, (dilatation and hypokinesis is reversible in this case), consequences of long-term hyperkinetic circulation (anemia, high dialysis access flow volume). In extreme cases, hyperkinetic heart failure develops. Fortunately, the dilatation and dysfunction due to hyperkinetic circulation are usually reversible – after correction of anemia or flow-reducing surgery of the dialysis access.
Regional wall motion abnormalities (RWMA) develop as a result of coronary artery disease – similarly to the general population. Moreover, RWMAs develop in some patients during hemodialysis and last for several hours after it. Physiologically, regional left ventricular stunning explains these intradialytic RWMAs. One study [17] explains the development of intradialytic RWMAs by the global myocardial hypoperfusion during hemodialysis, which occurs even in patients without significant stenosis on coronary angiography. The same group has shown that in patients with known repeated dialysis induced RWMAs, the left ventricular ejection fraction decreases by 10% within one year [18]. RWMAs developed more frequently in patients suffering from intradialytic hypotension. The latter could be a result of inadequate (too low) estimation of patient's dry weight, of impaired autoregulatory mechanisms due to autonomic dysfunction, but also due to excessive heating of the dialysis solution: Jefferies et al. showed that individualized setting of dialysis solution temperature (mean 36.0 8C) in comparison to automatic setting to 37.0 8C led to a significant reduction of RWMAs – authors suggested that the lower temperature prevents systemic vasodilatation with subsequent hypotension [19]. Echocardiographic criteria: according to the common European-American Guidelines, the normal end-diastolic left ventricular diameter is 42.0–58.4 mm in males and 37.8– 52.2 mm in females, normal end—diastolic volume (LVEDV) calculated by the modified Simpson method and indexed to body surface area is 34–74 ml/m2 in males and 29–61 ml/m2 in females [20]. These values were derived from the healthy population. Hickson et al. [4] used the upper value of normal LVEDV 86 ml/m2 or systolic volume above 37 ml/m2. Other studies used different cutoff values. The problem in ESRD patients is significant LVEDV dependency on the actual hydration, in other words in the time delay since the previous hemodialysis. According to our opinion, this time delay should be at least 24 h, if the increased central venous pressure is not assessed by inferior vena cava (Table 2). Ejection fraction quantification should be performed by planimetry according to the guidelines [12], RWMAs – if present – should be described by the segmental analysis of contractility. Some authors use special wall motion score. Dialysis-induced RWMAs could be distinguished from other RWMAs due to coronary artery disease by another echocardiography with longer time delay since the previous hemodialysis. Prognostic impact: left ventricular dilatation was linked to poorer prognosis only in some studies. Clear increase of mortality is linked to left ventricular systolic dysfunction. The highest mortality affects patients with the systolic dysfunction of both ventricles [4]. Patients with dialysis induced RWMA are at risk of faster systolic function decline [18]. From the practical point of view, we recommend coronary angiography in case of the first RWMA occurrence with possible revascularization.
Left ventricular diastolic dysfunction The term ‘‘diastolic dysfunction’’ includes the issues of both left ventricular relaxation and compliance and also increased filling pressures.
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Etiopathogenesis: frequent LVH brings conditions for the development of diastolic dysfunction in ESRD patients. The filling pressures are also significantly influenced by hydration and thus change with the phase of hemodialysis therapy. Echocardiographic criteria: according to the current Guidelines, the evaluation of left ventricular diastolic dysfunction should be based primarily on the E/A ratio of transmitral flow, on tissue Doppler examination of the mitral annulus, on left atrial volume and on the gradient of tricuspid regurgitation [21]. The former combination of criteria is the stumbling block of diastolic function estimation in hemodialyzed patients: (1) the height of E wave is mainly influenced by the actual hydration (left ventricular preload); (2) the movement of the lateral part of mitral annulus is frequently limited by the present calcification and less data is available for the septal part; (3) left atrial dilatation is very frequent in ESRD patients especially due to (cyclic) overhydration; (4) pulmonary hypertension is also very frequent, but because of other mechanisms explained below. Besides these parameters, the presence of LVH should be also taken into account. Diastolic dysfunction was observed in up to 50% of hemodialyzed patients. Pragmatically, we frequently assume that the diastolic dysfunction is present and we attempt at least to estimate the filling pressures. They are without any doubt increased in restrictive type of transmitral flow, in high values of E/e0 ratio above 14. The actual estimation of central venous pressure should be taken into account. Prognostic impact: long-term increase of the filling pressures increases both the number of cardiovascular complications and mortality [22].
Left atrial dilatation and dysfunction Left atrium is the most frequently dilated cardiac cavity. Etiopathogenesis: the left atrial wall is very thin; therefore the left atrium is prone to volume induced changes – especially to cyclic hyperhydration in chronically hemodialyzed patients. Other mechanisms of left atrial dilatation include the left ventricular diastolic dysfunction, less frequently also disease of the aortic and mitral valves. Functionally, the left atrium plays 3 functions: (1) pump function, which contributes to the left ventricular filling at the late diastole; (2) reservoir functioncollection of the blood, which continuously flows from the pulmonary veins; (3) conduit function in the early diastolic phase. Left atrial dilatation and dysfunction lead to atrial fibrillation, which leads to further dilatation. Echocardiographic criteria: the cross-sectional left atrial diameter was measured in the parasternal view, then the atrial length and width in the apical 4 chamber view. Nowadays, planimetric calculation of the left atrial volume is preferred and indexed to body surface area (upper normal value is 34 ml/m2. Alternatively, 3D examination of the left atrial volume is used, but this method is prone to good visualization. Left atrial ejection fraction could be calculated by planimetry similarly to the left ventricular ejection fraction. Prognostic impact: some studies have shown higher cardiovascular morbidity of ESRD patients with dilated left atrium [23]. Left atrial ejection fraction decreases together with age and longer dialysis vintage [24].
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Right ventricular dysfunction Etiopathogenesis: right ventricular dysfunction is usually the result of pulmonary hypertension. Other factors include cyclic overhydration, higher dialysis arteriovenous access flow, coronary artery disease and, less frequently, primary disease of the right heart valves. Right ventricular dysfunction could negatively influence the function of the left ventricle by the mechanism of interdependence (especially the left ventricular filling is impaired). Echocardiographic criteria: the cross-sectional right ventricular diameter in the parasternal long axis view was traditionally used for the assessment of its size. However, this parameter is the most variable, which comes from the foolish attempt to measure the cross section of a triangle (the right ventricle has almost this shape in this view). The most accurate assessment of the right ventricle size in comparison to cardiac magnetic resonance is the calculation of area in the apical 4 chamber diastolic view. Other used parameters include cross-sectional basal diameter at the level of tricuspid valve annulus and in the mid-length of the right ventricle – see Fig. 1. Performed trials in ESRD patients used only some parameters of right ventricular systolic function – especially TAPSE (tricuspid annular plane systolic excursion) and systolic velocity of tricuspid annulus in tissue Doppler examinations. This selection is logical – although the right ventricle has 3 muscle layers (longitudinal, radial and spiral), longitudinal shortening plays the most important role. European and American guidelines recommend also the use of the right ventricle myocardial performance index (RIMP – right ventricle index of myocardial performance, also called Tei index). The latter includes both systolic and diastolic time interval (isovolumic contraction time + ejection time + isovolumic relaxation time – see Fig. 2. Another parameter mentioned by the guidelines [20] is the fractional right ventricle area change (FAC), which could be calculated similarly to ejection fraction after getting enddiastolic area (EDA) and end-systolic area (ESA) from apical 4-chamber view, resp. from the modified view concentrated
Fig. 1 – Most frequently used parameter of right ventricle size. Apical 4 chamber view: measurement of enddiastolic area (EDA), basal diameter (at the level of tricuspid annulus) and mid-diameter is depicted.
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Fig. 2 – Tei index of the right ventricle. RIMP (right ventricle index of myocardial performance) called also Tei index of the right ventricle – usage of the tissue Doppler assessment of the lateral part of the tricuspid annulus. It is used according to the following equation: RIMP = (IVRT + IVCT)/ET = (TCO-ET)/ET. Abbreviations: IVRT, isovolumic relaxation time; IVCT, isovolumic contrationtime; TCO, tricuspid valve closure to opening time; ET, ejection time. The inclusion of the systolic phase (isovolumic contraction and ejection duration) and diastolic phase (duration of isovolumic relaxation, which is one of the diastolic function descriptors), means that Tei index assess right ventricular performance globally. However, it is unreliable when the right atrial pressure is increased [20].
on the largest part of the right ventricle. On the contrary, calculation of right ventricular volume and ejection fraction is difficult by 2D echocardiography, because the right ventricle has a complex shape similar to a pyramid. First data about the ejection fraction calculation by 3D echocardiography are available. Global longitudinal right ventricular strain is also used – some authors calculate it only from the free wall, others include also the interventricular septum [12]. If the latter method is used, the obtained value is lower (resp. less negative). Details of the correct assessment of the size and function of right-sided heart structures are explained in the recent book [25] (in Czech language), or in the guidelines [20]. Prognostic impact: right ventricular dysfunction is linked to increased mortality of ESRD patients [4], even higher risk brings the dysfunction of both ventricles.
Pulmonary hypertension Etiopathogenesis: pulmonary hypertension is defined as the increase of pulmonary artery mean pressure above 25 mmHg. It affects up to 50% of ESRD patients [26]. Many mechanisms have been described: the influence of uremic toxins on the pulmonary arteries (increased oxidation stress, endothelial dysfunction, vitamin D deficit, etc.), left-sided heart disease, cyclic overload, hyperkinetic circulation as a result of anemia and of dialysis arteriovenous access, thromboembolism
(including thrombi released during thrombolysis of the dialysis access), sleep apnoea syndrome and others. Echocardiographic criteria: thanks to it non-invasiveness, echocardiography plays a fundamental role in the pulmonary hypertension diagnosis, despite this method possess some pitfalls [25]. Morphological signs of pulmonary hypertension include right ventricular and atrial dilatation, dilatation of the common pulmonary trunk (seen in the parasternal short axis view) above 25–30 mm, interventricular septal flattening (continuous left ventricular D-shape is the extreme), and inferior vena cava dilatation. Functional signs include the pulmonary artery acceleration time shortening below 100 ms or dicrotic notch in its deceleration phase (so called type III flow), the presence of regurgitation on right-sided valves. The estimation of the actual pressure in the pulmonary artery is usually derived from the peak gradient of the tricuspid regurgitation. The estimated value of the central venous pressure should be added to the peak gradient (see Table 2) to get the systolic right ventricular pressure (which is equal to the systolic pulmonary artery pressure) supposing that the pulmonary valve stenosis is excluded. From the practical point of view, it should be stressed out that only high quality regurgitation wave from the spectral Doppler should be used for analysis. Another problem brings severe tricuspid regurgitation – in this case there is fast equalization of the ventricular and atrial pressures – therefore, the measured peak gradient underestimates the actual systolic pressure. Analogically, the systolic pulmonary artery pressure (PASP) can be derived from the maximal gradient of pulmonary regurgitation and the minimal gradient for the estimation of the diastolic pulmonary artery pressure (PADP). Some authors use more complicated approach for the estimation of the mean pulmonary pressure (MAP), such as MAP = PASP/3 + 2PADP/3. Prognostic impact: the presence of pulmonary hypertension increases considerably and significantly all-cause mortality of CKD (including ESRD) patients.
Extraosseal calcification Extraosseal calcification affects many organs, including heart and arteries. Etiopathogenesis: vascular calcification appears already in CHD stage 3. Pro-calcification factors include high levels of calcium, high levels of phosphates, hyperparathyreosis and FGF-23. On the contrary, there are protecting factors, such as fetuin and vitamin K-dependent GLA protein – the risk of calcifications is therefore increased by the warfarin therapy (warfarin is a vitamin K antagonist). The calcification of intima and media is an irreversible active process similar to bone formation – phenotype transformation of myocytes to osteoblast-like cells develops. Calcification of the medial wall layer (mediocalcinosis) leads to increased arterial wall rigidity and lumen narrowing. As a result, organ ischemia develops. In extreme cases, the calcification spread to the cardiac valves with the development of stenotic valvular disease (especially of aortic and mitral valves). Interestingly, there are some common mechanisms of myocardial calcification and of LVHFGF-23 is involved in both states. This factor is produced by osteocytes and physiologically it increases renal phosphate
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Fig. 3 – Advanced heart calcification. Parasternal liongaxis view. There is advanced calcification of mitral annulus, leaflets and of chordae tendineae, of aortic annuls and leaflets and of the septal endocardium of the left ventricle. This patient suffered from severe aortic and mitral stenoses, both valves have been successfully replaced.
excretion – however, renal phosphate excretion decreases with the progression of CKD. The rise of FGF-23 levels precedes the rise of parathormone and both these molecules play a role in the development of extraosseous calcifications. Increased FGF-23 level is also a predictor of cardiovascular complications. Besides its effect on the development of calcifications, FGF-23 possess many other unfavorable effects – it increases production of inflammatory cytokines, accelerates both the development of CKD and of LVH, affect immune mechanisms, damages endothelium [27]. Echocardiographic criteria and prognostic impact: a number of heart calcification schemes have been developed to describe the calcification load. The simplest ones differentiate 3–4 stages and calculate calcifications of the mitral annulus, mitral valve leaflets and both annulus and cusps of the aortic valve. The most detailed is the recently developed ‘‘Global calcification score’’ with the maximum of 12 points: up to 3 points for the affection of the mitral annulus (each third 1 point), posterior leaflet movement restriction (1 point), leaflet calcification (0–2 points), calcification of the subvalvular apparatus (1 point), of aortic valve cusps (up to 3 points) and affection of the aortic valve annulus (1 point). A recent study revealed almost linear relation between heart calcification score and total mortality + risk of ischemic stroke [28]. Calcification could affect heart valves (Fig. 3). It is necessary to highlight higher sensitivity and preciseness of computerized tomography in the assessment of cardiac calcifications.
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Fig. 4 – Arteriovenous dialysis access flow volume calculation by ultrasonography. The calculation should be performed in the brachial artery in case of native arteriovenous fistulas and in the graft (far from arterial anastomosis) in case of arteriovenous grafts (this case). Vascular diameter and time-averaged mean velocity (TAMEAN – green curve) is measured. The calculation is based on the following equation: Q = pr2 T TAMEAN, where Q = flow volume, r = radius. This equation is a part of many ultrasound devices, but frequently as an option. For the manual calculation, we should use the radius in centimeters, velocity in cm/s and magnify the result by 60. Then we get flow volume in ml/min.
stenosis development is accelerated in CKD patients, which is also true for biological heart valves. Echocardiographic criteria: the same criteria as in the common population are used. It is important not to rely on the pressure gradients of stenotic valves: hyperkinetic circulation is frequent in ESRD patients especially due to arteriovenous dialysis access – therefore, the pressure gradients overestimate the hemodynamic impact. Calculations based on continuity equation should be preferred.
Pericardial diseases Pericardial effusion was a frequent finding in ESRD patients in 1970s. Thanks to the improvements in hemodialysis therapy it is now rare and occurs only in patients coming ‘‘from the street’’ and in some subjects suffering from a systemic disease, such as lupus erythematosus, etc. Some studies observed pericardial thickening in ESRD patients. Nevertheless, computerized tomography is more precise in this aspect [29]. Such thickening could influence ventricular filling and resulting constrictive pericarditis was also described [30].
Valvular disease Etiopathogenesis: valvular disease develops in CKD patients thanks to similar mechanisms that occur in general population. Regurgitation of atrioventricular valves is more frequent due to volume overload. Degeneration of the valves and
The effect of a single hemodialysis session on echocardiographic parameters Hemodialysis alters fast and considerably milieu interieur, especially in anuric patients, it decreases body water volume
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and, therefore, also blood pressure. These mechanisms are mirrored by the changes of echocardiographic parameters, as could be observed if we perform 2 examinations: before and after hemodialysis. In the vast majority of patients, the fall of water volume and blood pressure leads to the decrease of atrial and ventricular volumes, of the filling pressures, of the regurgitant valve disease severity. Cardiac output and pulmonary artery pressure also decrease [24,31]. Some patients develop already mentioned RWMAs during hemodialysis. Similarly, arteriovenous access flow volume is also lower. However, some 5–10% of patients react ‘‘paradoxically’’: their cardiac output increases as well as the pulmonary artery pressure and arteriovenous access flow. It is typical for patients with water overload-usually unable to follow fluid intake restrictions, when the heart autoregulatory mechanisms are exhausted. Left ventricular unloading during hemodialysis probably plays a role in the increase of cardiac output and related parameters, but the exact mechanisms are not yet described in detail. We also observe worsening of mitral regurgitation in some patients after hemodialysis. It is probably due to intradialytic RWMA, leading to mechanisms similar to ischemic mitral regurgitation. So when should be echocardiography performed in hemodialysis patients? Ideally at least 24 h after the previous hemodialysis when we can already expect equilibrium between intravascular and extravascular hydration. From the practical point of view, it is important also because the echographic visibility is worse shortly after hemodialysis.
The effect of arteriovenous access flow volume Functioning vascular access is necessary for hemodialysis. Performed studies confirmed that the best option is the native arteriovenous shunt (‘‘fistula’’) – patients with this type of access suffer from significantly less complications and have longer life expectancy than patients with arteriovenous (polytetrafluoroethylene) graft or dialysis catheter. Flow volume 500–1500 ml/min is considered ‘‘normal’’ or ‘‘usual’’ (they represent 10–30% of resting cardiac output!). However, not exceptionally, the flow volume reaches 2–5 l/min! Subsequent complications are therefore not surprising for cardiologists [32]. After the creation of arteriovenous access, blood pressure decreases and levels of B-natriuretic peptide increase, the volume of heart cavities is larger, left ventricular diastolic function worsens as well as the severity of regurgitant valve disease. Some patients with high-flow access hand ischemia and/or hyperkinetic heart failure develops. The increase of cardiac output secondary to high access flow leads to the increase of pulmonary artery pressure. According to our experience, the majority of ESRD patients referred to our Cardiocenter for pulmonary hypertension, had high-flow access. After the surgical flow correction the estimated pulmonary systolic pressure decreased by 10–40 mmHg (own unpublished data). Vascular access flow volume also contributes to the decompensation of classic congestive heart failure, but the effect is very individual. Vascular access flow volume could be measured using dilution techniques at the hemodialysis units or with the use
of linear (‘‘vascular’’) ultrasound probe at the brachial artery – similarly to cardiac output measurement in the left ventricular outflow tract (Fig. 4). Due to all aforementioned reasons, it is desirable for the cardiologist to be aware of arteriovenous access flow volume in the majority of cardiac pathologies – surgical access flow reduction is not only easier than cardiac surgery, but in many patients it is the causal therapy. On the other hand, it should be mentioned that many patients tolerate high access flow very well. This is why the asymptomatic high access flow is left without intervention and in many countries it is even not an indication to echocardiography. According to our opinion, such patients should be examined by echocardiography every 6–12 months and in case of ventricular dilatation/dysfunction or pulmonary hypertension development, the patient should be indicated to flow reducing surgery.
Conclusions, what should the examination report contain The main feature of echocardiographical examinations of ESRD patients treated by hemodialysis is the dependency of many parameters on actual hydration and sometimes also on arteriovenous access flow volume. These include diameters/ volumes of cardiac cavities, filling pressures, estimated pulmonary artery pressure, severity of valvular disease. Appropriate setting of dry weight is complicated and according to our experience it is sometimes over- or underestimated even by kilograms (liters of water). Therefore, the necessary requirement for the echocardiographer examining CKD/ESRD patients is the estimation of actual hydration (central venous pressure), time delay since the previous hemodialysis (>24 h advisable) and the presence or absence cardiac calcifications should be also mentioned. We recommend also the quantification of vascular access flow volume especially if it is not measured at the hemodialysis units. Close cooperation of nephrologists and cardiologists is beneficiary for the patients. An example of such cooperation is the Cardionephrology department of the Complex Cardiovascular Center, General University Hospital, Prague, where the patients are examined simultaneously by a cardiologist and by a nephrologist.
Conflict of interest None declared.
Ethical statement Authors state that the research was conducted according to ethical standards.
Funding body None.
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Please cite this article in press as: J. Malík et al., Echocardiography in patients with chronic kidney diseases, Cor et Vasa (2017), http://dx. doi.org/10.1016/j.crvasa.2017.07.008