Abstract
Objectives
Heart failure is associated with higher mortality of hemodialysis patients. Fluid overload is a major risk factor for cardiovascular disease in these patients, but it is frequently clinically silent. The optimal assessment of ideal dry weight is still searched for. We hypothesized that even very mild fluid overload would be associated with the left ventricular ejection fraction and on the size of heart chambers.
Methods
Inclusion visit data of a cohort observation study were analyzed: bioelectrical impedance, echocardiography with hemodynamic estimations and basic laboratory tests. Fluid overload was defined by using the fluid overload/extracellular water index (FO/ECW, relative hydration index) > median value. Moreover, analyses according to FO/ECW quartiles were performed. All these measurements were done within an hour and at least 24 h after the previous hemodialysis.
Results
We included 334 patients. FO/ECW median was 7%. Patients with fluid overload had lower left ventricular ejection fraction (median (interquartile range): 53(45–62) vs. 60(56–67)%, p = 0.0002), dilatation of all heart chambers, more pronounced hypertrophy of the left ventricle with higher NTproBNP, significantly lower serum albumin levels and lower body mass. The relationship between the relative hydration index and heart changes was gradual. Fluid overload, as defined by the mild criteria, was associated with a worse ejection fraction, but also with other functional and structural heart changes.
Conclusions
Our study demonstrates that in patients on dialysis, even mild (often subclinical) fluid overload is associated with structural and functional heart changes. Early identification of fluid overload with improved methods of volume assessment is thus warranted and especially in lean patients.
Keywords: Fluid overload, haemodialysis, bioimpedance, serum albumin, NTproBNP, heart failure
Introduction
Cardiovascular complications are the leading cause of death in patients with end-stage kidney disease (ESKD) on hemodialysis (HD) [1]. Cyclical overhydration between hemodialysis sessions is a typical feature of patients treated by this renal replacement modality. Chronic overhydration is linked with inadequate dry weight setting and/or limited patient′s compliance. It is not rare [2] and is associated with increased risk of cardiovascular complications (such as hypertension, higher arterial stiffness, and left ventricular hypertrophy) [3] and with higher mortality [2]. Moreover, aggressive fluid removal during a hemodialysis session can induce circulatory stress and multi-organ injury [4], and it manifests as intradialytic hypotension, a feature that also increases the mortality of patients on chronic hemodialysis [5].
In clinical practice, the management of fluid volume balance and dry weight assessment is based on blood pressure, interdialytic weight gain, cardiac function, nutritional status, and different comorbidities. Subjective evaluation of patient’s signs and symptoms prevails over the objective measurements [6]. Clinical evaluation has been repeatedly shown to have limited diagnostic value for detecting volume overload and interstitial edema in hemodialysis patients. Several diagnostic methods have been developed for estimating the total fluid content, including bioimpedance techniques, lung ultrasonography, inferior vena cava diameter measurement, echocardiography, biochemical parameters (BNP/NT-proBNP), chest X-ray) [7]. Each of these different methods has its strengths and limitations [7]. The combination of clinical judgment and bioimpedance is currently mostly used for dry weight assessment although the Kidney Disease Outcomes Quality Initiative (K/DOQi) guidelines do not include recommendations for the diagnosis of fluid overload by objective methods [8] and different bioimpedance devices give different results [9]. Bioimpedance identifies total body water (TBW), intra- and extracellular water (ICW, ECW), fluid overload (FO) and other parameters.
Echocardiography is a widely available method giving a precise description of heart structures, their sizes and function. Moreover, it allows haemodynamic estimations, such as pulmonary arterial systolic pressure, systemic vascular resistance, etc. Also, bidirectional changes of the ejection fraction after a single hemodialysis were observed (increase and decrease) [8]. This is probably due to changes in left ventricular filling pressures and in its afterload. Although the links between volume and cardiovascular mortality were reported, the direct comparisons of bioimpedance and echocardiography data are sparse [10].
We hypothesized that even very mild fluid overload would have a gradual negative impact on the left ventricular systolic function and on the size of the heart chambers. Therefore, we performed a cross-sectional analysis of the inclusion visits of the CZecking HF-CKD trial with the use of the combination of bioimpedance, detailed echocardiography, and fistula flow calculation in patients on chronic hemodialysis to investigate the cardiovascular effects of hyperhydration, specifically, to reveal the links between different levels of fluid overload and left ventricular systolic function. Moreover, the links between fluid overload and other structural and functional heart changes were also evaluated.
Materials and methods
Study population
Data from the first/inclusion visit of the prospective ongoing trial ‘CZecking HF-CKD’[11] performed till 1 March 2024 were used for the purpose of this cross-sectional analysis. We included patients who undergo hemodialysis at any of the 7 collaborating hemodialysis units and fulfill the broad inclusion criteria, such as willingness to participate and life expectation >6 months and lack of a living kidney transplant donor. In patients with a history of kidney transplantation and on hemodialysis at the time of inclusion, we calculated the total time that the patient spent of hemodialysis. The list of examinations included bioelectrical impedance analysis, echocardiography with hemodynamic estimations (see below for details), AVF flow calculation, and basic clinical data and laboratory examinations. All these measurements were done within an hour and 24–36 h after the previous hemodialysis. Blood pressure was measured using an automatic sphygmomanometer (Omron M6, Omron, Japan). Basic laboratory data included blood hemoglobin, total protein, albumin and NTproBNP. Hemodialysis settings, including target weights and ultrafiltration requirements were not changed prior to the inclusion of the patients. They were based on a combination of clinical judgment and bio-impedance analysis.
The study was approved by the Ethical Committee of the General University Hospital in Prague on 18th February, 2021 (reference number 1/21), and is registered in ISRCTN database (No. 18275480). We explained the principles of the study to all patients, and they signed informed consents. The study conforms with the Declaration of Helsinki.
Bioimpedance spectroscopy
We used a Body Composition Monitor (BCM, Fresenius, Germany) with electrodes placed on the side without arteriovenous hemodialysis access. Patients with pacemakers, larger bilateral joint replacements, or after major amputations were included into the study, but not analyzed in this analysis. BCM identifies a number of parameters, but we used only total body water (TBW) and fluid overload/extracellular water index (FO/ECW) – see below for the purpose of this analysis.
Arteriovenous access flow measurement
Blood flow volume (Qa) of the arteriovenous fistula (AVF) or arteriovenous graft (AVG) was measured by a linear probe of the ultrasonography Vivid E9 or E95 device (General Electric, Vingmed, Norway). In AVGs, we measured the vascular access flow directly in the graft. The vascular access flow in native AVFs was measured in brachial artery no matter which artery is feeding the vascular access as described earlier [12]. In patients with central venous catheters we used the value 0 mL/min for access blood flow.
Echocardiography
Echocardiography was performed using a matrix echocardiography probe of Vivid E9 or E95 device (General Electric, Vingmed, Norway), and included detailed analysis of the volumes of heart cavities, quantification of valvular disease and diastolic dysfunction according to the recent guidelines [13], and cardiac output (CO) calculation (using the left ventricular outflow tract diameter and velocity time interval). Central venous pressure (CVP) was estimated using the inferior vena cava end-expiratory diameter and respiratory collapsibility [13]. Examinations were performed by one of 3 examiners experienced in cardio-nephrology (J.M, A.V. and K.B.S.).
Calculations
Mean arterial pressure (MAP) was calculated by the following formula: MAP = 1/3 of the systolic blood pressure + 2/3 of the diastolic blood pressure. Although BCM gives the value of ‘overhydration’ (in fact, it is fluid overload), it is not indexed for body size. Therefore, we calculated FO/ECW index (which is reported as the relative hydration index or OH/ECW in some studies). Effective cardiac output (COef) was calculated as the difference of the total cardiac output and AVF flow volume (Coef = CO – Qa). Total vascular resistance (TVR) was calculated as follows: TVR = (MAP − CVP)/CO, where MAP = mean arterial pressure, CVP = central venous pressure and CO = cardiac output. Analogically, we calculated the systemic vascular resistance (SVR), only with the use of the effective cardiac output. Thus, SVR excludes AVF flow. Both TVR and SVR are presented in dynes⋅sec⋅cm−5. TVR was also normalized (indexed) to the body surface area (TVRI) and is presented in dynes.s.cm−5.m2.
Statistical analysis
All continuous data were tested for their distribution and found non-Gaussian. Therefore, we expressed the results as median(interquartile range) and used Mann–Whitney U test for the group comparisons and Spearman’s rank correlation analysis for testing the relations between variables. Moreover, similar comparisons were performed for quartile values in selected results. Calculations were performed using the STATISTICA software, and p-values < 0.01 were considered significant.
Results
Out of 349 patients selected into the study, 334 patients (without pacemaker or after major amputation) were included into this analysis (209 males and 125 females), aged 69.5 (57.3–76.9) years, dialysis vintage 24.0 (6–67) months. The most common etiologies of ESKD were: diabetic nephropathy (29.6%), hypertensive nefrosclerosis (25.9%), chronic tubulointerstitial nephropathy (8.6%), polycystic kidney disease (8.1%), IgA nephropathy (4.9%) and bilateral nephrectomy (4%). Hemodialysis vascular access was an arteriovenous fistula in 73%, an arteriovenous graft in 19%, and a catheter in 8%.
FO/ECW ratio median was 7% in our study, and subjects with >7% were considered overhydrated/having fluid overload for the purpose of this analysis. Twenty-four percent of the patients had FO/ECW >14%. Patients with fluid overload had higher NTproBNP, but also a gradual decrease of the left ventricular ejection fraction and other changes, see Table 1 and Figures 1 and 2 for details. Shortness of breath level did not differ between groups (median NYHA II in both of them). Patients with fluid overload had significantly lower albumin levels and lower body mass index, as presented in Table 1.
Table 1.
Differences between patients with and without fluid overload.
| FO/ECW <7% | FO/ECW >7% | P-value | |
|---|---|---|---|
| Age (years) | 68.8 (54.9–77.8) | 72.7 (62.2–79.2) | 0.19 |
| Dialysis vintage (months) | 20 (6–48) | 37 (10–84) | 0.037 |
| Systolic BP (mmHg) | 134 (123–149) | 135 (115–154) | 0.62 |
| Diastolic BP (mmHg) | 75 (67–82) | 76 (64–85) | 0.90 |
| MAP (mmHg) | 95 (88–103) | 97 (82–109) | 0.93 |
| Heart rate (1/min) | 71 (65–81) | 71 (64–80) | 0.60 |
| Body mass index (kg/m2) | 27.1 (24.0–31.6) | 24.0 (21.1–27.1) | <0.0001 |
| Body surface area (m2) | 1.91 (1.71–2.08) | 1.87 (1.70–2.01) | 0.15 |
| AVF flow (mL/min) | 980 (610–1300) | 1000 (690–1493) | 0.60 |
| LV EF (%) | 60 (56–67) | 55 (45–62) | 0.0002 |
| LVMi (g/m2) | 66 (46–101) | 92 (52–119) | 0.006 |
| LVEDV (ml) | 97 (76–122) | 111 (91–147) | 0.0006 |
| Diastolic dysfunction grade | 1 (0–2) | 2 (1–2) | 0.003 |
| Cardiac output (L/min) | 6.0 (4.7–7.1) | 5.9 (4.8–6.8) | 0.76 |
| COef (L/min) | 4.81 (3.87–5.98) | 4.75 (3.89–5.67) | 0.38 |
| Cardiac index (L/min/m2) | 3.13 (2.68–3.60) | 3.17 (2.65–3.57) | 0.84 |
| CIef (L/min/m2) | 2.52 (2.19–3.01) | 2.52 (2.11–2.94) | 0.65 |
| LAVi (ml/m2) | 35.0 (26–45) | 44 (35–58) | 0.0001 |
| RVEDA (cm2) | 18 (16–22) | 22 (19–28) | 0.0002 |
| TAPSE (mm) | 24 (21–28) | 24 (19–28) | 0.29 |
| RAEDV (ml) | 44 (32–64) | 70 (52–88) | 0.0003 |
| FAC (%) | 48 (40–53) | 41 (31 - 48 | 0.008 |
| CVP (mmHg) | 4 (3–7) | 8 (4–13) | <0.0001 |
| SVR (dynes⋅s⋅cm⁻5) | 1249 (1093 - −1494) | 1294 (1015–1532) | 0.83 |
| TVR (dynes·s·cm⁻⁵) | 1550 (1237–1975) | 1645 (1221 –1938) | 0.94 |
| TVRi (dynes·s·cm⁻⁵⋅m2) | 2846 (2385–3464) | 2884 (2261–3576) | 0.84 |
| NTproBNP (ng/L) | 2656 (1569–7458) | 10579 (4432–30445) | <0.0001 |
| Hemoglobin (g/L) | 111 (103–118) | 109 (101–117) | 0.38 |
| Total blood protein (g/L) | 66.2 (63.1–70.0) | 64.9 (60.0–68.0) | 0.026 |
| Albumin (g/L) | 40.0 (37.8–41.5) | 38.0 (36.0–40.0) | 0.0009 |
| Total body water (L) | 38.2 (31.8–44.1) | 36.8 (31.1–41.0) | 0.08 |
Data are presented as median (interquartile range).
BP: blood pressure; MAP: mean arterial pressure; LV EF: left ventricular ejection fraction; LVMI: left ventricular mass index (to body surface area); LVEDV: left ventricular end-diastolic volume; LAVi: left atrial volume index (to body surface area); RVEDA: right ventricular end-diastolic area; TAPSE: tricuspid annular plane systolic excursion; RAEDV: right atrial end-diastolic volume; FAC: fractional area change (of the right ventricle); CVP: central venous pressure; NTproBNP: N-terminal pro-brain natriuretic peptide; CO ef: effective cardiac output; CIef: effective cardiac index; TVR: total vascular resistance (including arteriovenous fistula flow); TVRI: TVR indexed to the body surface area; SVR: systemic vascular resistance (calculated from COef.).
Figure 1.
Gradual increase of heart cavities according to FO/ECW quartiles. LVEDV: left ventricular end-diastolic volume; LAVi: left atrial end-diastolic volume indexed for body surface area; RVEDA: right ventricular end-diastolic area; RAEDV: right atrial end-diastolic volume. Boxes represent median and 25th–75th percentiles. Horizontal bars represent statistically significant differences between quartiles (p < 0.05).
Figure 2.
Dependence of ejection fraction on the FO/ECW ratio. LVEF: left ventricular ejection fraction. Boxes represent median and 25th–75th percentiles. Horizontal bars represent statistically significant differences between quartiles (p < 0.05).
In the Spearman rank correlation analysis, FO/ECW ratio was directly related to the sizes/volumes of both atria and ventricles, to NTproBNP, left ventricular mass index and to the grade of diastolic dysfunction. It was inversely related to the ejection fraction, body mass index, albumin and total protein; see Table 2 for details. Albumin level was significantly directly related to hemoglobin (rho = 0.26, p < 0.0001), and indirectly to age (rho = −0.2, p = 0.0004) and NTproBNP (rho = −0.22, p = 0.0006). Neither significant relation between serum albumin nor the left ventricular ejection fraction or cardiac output or index was present. Body mass index was directly related to cardiac output (rho = 0.26, p < 0.0001), to the size of both ventricles (rho 0.17, p = 0.002 and rho − 0.23, p = 0.003, for the left ventricular end-diastolic volume and right ventricular end-diastolic area, respectively) and indirectly to NTproBNP (rho = −0.23, p = 0.0001), but not to the left ventricular ejection fraction, nor to the cardiac index. Albumin and body mass index were not significantly interrelated.
Table 2.
Relation of the relative hydration index (FO/ECW) to other variables.
| Rho | p-value | |
|---|---|---|
| Age | 0.06 | 0.40 |
| Dialysis vintage | 0.12 | 0.11 |
| Body mass index | −0.39 | <0.00001 |
| AVF flow | 0.03 | 0.71 |
| LV EF | −0.32 | <0.00001 |
| LVMi | 0.20 | 0.006 |
| LVEDV | 0.27 | 0.0002 |
| CO (L/min) | −0.03 | 0.64 |
| LAVI | 0.33 | <0.00001 |
| RVEDA | 0.40 | 0.00002 |
| TAPSE | −0.06 | 0.44 |
| RAEDV | 0.36 | 0.0002 |
| FAC | −0.25 | 0.008 |
| Central venous pressure | 0.39 | <0.00001 |
| NTproBNP | 0.46 | <0.00001 |
| Hemoglobin | −0.07 | 0.36 |
LV EF: left ventricular ejection fraction; LVMI: left ventricular mass index (to body surface area); LVEDV: left ventricular end-diastolic volume; LAVi: left atrial volume index (to body surface area); RVEDA: right ventricular end-diastolic area; TAPSE: tricuspid annular plane systolic excursion; RAEDV: right atrial end-diastolic volume; FAC: fractional area change (of the right ventricle); CVP: central venous pressure; NTproBNP: N-terminal pro-brain natriuretic peptide.
Discussion
We hypothesized that even very mild fluid overload would have a gradual negative impact on the left ventricular systolic function and on the size of the heart chambers. This hypothesis was true: mild fluid overload is related to the dilatation of all heart cavities, the left ventricle has a lower ejection fraction, is more hypertrophied, and had a worse diastolic function. Moreover, we observed higher pulmonary arterial pressure. Patients with fluid overload also had more often heart failure, higher NTproBNP, lower body mass index and lower albumin levels. Patients with lower body mass index were more prone to fluid overload, which was mirrored by higher NTproBNP and vice versa. Moreover, higher BMI was linked to larger heart cavities and to higher cardiac output.
The inverse relation between FO/ECW and ejection fraction could be surprising at first sight, because, according to the Frank Starling mechanism, the left ventricular ejection fraction is linearly related to the filling pressures [14]. However, this mechanism works only within some limits defined by the length of the myofibrils: further increase of the filling pressure decreases the ejection fraction due to overextension of the myofibrils that prevents adequate contraction (right part of the Frank Starling curve). This was most probably the case of our patients with fluid overload. Higher filling explains also the enlargement of all cardiac cavities. Associated left ventricular hypertrophy and worse diastolic dysfunction suggest for a long-term hyperhydration [15]. On the contrary, failing and hypertrophied ventricles need sufficient filling pressure for ensuring cardiac output demands. Such patients require higher dry weight setting to avoid hypotension. Indeed, patients with heart failure were more prone to fluid overload in our study. Moreover, a significant part of the blood occurs in the splanchnic veins and abnormalities of its release contribute to intradialytic hypotension in such patients [16].
Dilatation of all heart chambers depended on the fluid overload. Figure 1 depicts a gradual increase according to the quartiles; especially the atrial dilatations were prone to even mild fluid overload.
The median value of FO/ECW was 7% in our study and it was used as the cutoff for fluid overload. Such cutoff was among the lowest values published (together with [17]). Other trials reported the following FO/ECW medians: 13.48% [18], 13.6% [19] and 8.6% [20]. As far as echocardiographic differences (Table 1) and notably lower ejection fraction in patients with fluid overload occurred even with OH/ECW cutoff 7% in our larger population study, they highlight the need for maintaining dry weight as low as possible. This is more apparent in the quartiles comparisons (Figure 1). Therefore, even mild/subclinical fluid overload was related to the structural heart changes. Our patients underwent standard hemodialysis (3times per week). More frequent hemodialysis sessions bring better volume control [21]. However, it is important to emphasize that in our study, patients were examined 24 h after their last hemodialysis session, whereas in other studies, bioimpedance measurements were typically performed immediately before dialysis. Therefore, patients with an OH/ECW ratio below 7% were likely volume contracted (i.e. had a negative volume overload), indicating that their clinically set dry weight was probably too low. It is well known that an excessively low dry weight setting can reduce residual diuresis. However, as shown in our study, this may have a beneficial effect on the heart, at least partially due to improved hypertension control [22].
Hypoalbuminemia is an important risk factor for increased morbidity and mortality in patients on dialysis. Hypoalbuminemia could result from haemodilution caused by chronic volume expansion [23], which looks probable since albumin decreased with hemoglobin in our study. Inverse relationship of serum albumin with fluid overload is typical for the malnutrition-inflammation complex syndrome – MICS [24]. Many characteristics of this syndrome were reported, but were mostly metabolic and endocrine [23]. As the fluid overload was related to higher left ventricular mass, right ventricular size, pulmonary arterial systolic pressure and to NTproBNP level, but to lower ejection fraction (Table 2), we are convinced that heart failure is another descriptor of MICS. Interestingly, more pronounced valvular calcification was reported in MICS [23,24]. Another study showed higher levels of inflammatory markers, alpha-1-acid glycoprotein and NTproBNP and lower levels of ejection fraction in patients undergoing HD [25]. Albumin also rose with blood hemoglobin and decreased with age in our study, suggesting more complex relationships.
The level of fluid overload was inversely related to body mass index in our study. Two possible explanations include malnutrition and too low dry weight setting. The latter is more probable since albumin was not significantly related to body mass index. The fact that obese patients were more de-hydrated is against the recent observation that obese patients with HFpEF have higher blood volume [26]. However, in the hemodialysis population, the amount of fluids is controlled by the dialysis staff that uses the goals of dry weight. Therefore, the most probable explanation is in the psychology of healthcare providers, who are more cautious in underweight patients while obese patients ask for dry weight lowering to become ‘less obese’. An alternative explanation is that in obese patients, the bio-impedance could technically under-estimate the amount of body fluid. Measurement of the waist to height ratio could make the results clearer, but it was not measured in this study. In our study, obese patients tended to be dehydrated, whereas lean individuals were more likely to exhibit fluid overload. This observation is consistent with previous findings that lower body mass is associated with both volume overload and increased mortality in dialysis patients [26,27]. It can be speculated that a reversed clinical bias among healthcare providers may influence the determination of dry weight in lean patients, potentially leading to insufficient fluid removal.
The main limitation of this analysis is its cross-sectional character, since it included only data of the inclusion visits. Another limitation is that the sodium balance was not analyzed in this study. Our study differs from similar studies [17–20] in terms of the time delay since previous hemodialysis (24–36 h). Since volume status was assessed 24–36 h after dialysis, it is not possible to determine precisely how many patients actually reached normovolaemia immediately after the session (or even were volume contracted) at the end of the dialysis session. It is likely that our results underestimate the true proportion of patients who failed to achieve their target dry weight. This factor should be taken into account when interpreting the results, especially in comparison with studies in the literature where measurements are often performed immediately after the dialysis session. The strengths of this study are a larger number of included patients, examined prospectively, and all examinations occurred within a short time frame.
To summarize, fluid overload as defined by the mild criteria in our study was characterized by the worse left ventricular systolic function and heart chamber dilatations in our larger population cross-sectional study. Therefore, even mild fluid overload is related to the development of heart failure. Moreover, fluid overload was linked with higher pulmonary arterial systolic blood pressure and a more hypertrophied left ventricle with poorer diastolic function. Patients with fluid overload had more often heart failure, higher NTproBNP, lower body mass index and lower albumin levels. Hypoalbuminemia is not only a sign of malnutrition but also a marker of fluid excess and may be secondary to volume expansion conditions in dialysis patients. Taken together, as low as possible dry weight setting is warranted according to this study. Nevertheless, future prospective longitudinal trials are necessary to prove our results.
Funding Statement
This trial was supported by the grant No. NU22-02-00014 of the Agency of Health Research and by Ministry of Health, DRO 00064165, Czech Republic.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author [JM], upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author [JM], upon reasonable request.