4.1. Ca-125 in Overhydration
Carbohydrate antigen 125 (Ca-125) is a complex glycoprotein that is widely used in cancer diagnosis, especially ovarian cancer [
7]. It is mainly synthesized by mesothelial cells in the pericardium, peritoneum, or pleura [
7]. It is not known exactly why cells produce Ca-125, but it appears to be stimulated by inflammatory processes and mechanical injury [
1,
30]. It has recently emerged as a promising marker for congestive HF [
7]. As seen for New York Heart Association (NYHA) stage I/II to stage III or IV [
30], it increases with a decline in heart function. In the study conducted by Arik et al. considering various cancer markers and their correlation with kidney failure, only Ca-125 and Ca 19.9 were found to be significant. No correlation was found with PSA, AFP, or CEA [
50]. Ca-125 also alternates strongly with the diameter of IVC, as well as with the presence of fluid in the pleural cavity and peripheral edema [
7]. This phenomenon was investigated by Yilmaz et al. in patients with end-stage kidney disease [
1]. It correlated with the advancement of CKD, as well as with the levels of NT-pro-BNP and C-reactive protein and with a larger left ventricular end-diastolic diameter. The group of patients with a normal level of Ca-125 had higher albumin and hemoglobin levels compared to the group with elevated Ca-125. Serum NT-pro-BNP and Ca-125 were measured by a direct chemiluminescence assay. A correlation analysis between CA 125 levels and different parameters was performed, calculating Pearson’s or Spearman’s coefficient as appropriate.
p < 0.05 was considered statistically significant. The authors excluded patients with pleural fluid accumulation which could influence the Ca-125 serum level. Núñez-Marín et al. found no correlation between IVC and Ca-125, but in their study, the carbohydrate antigen was independently associated with a congestive pattern of intrarenal venous flow [
45]. This study also showed that not NT-pro-BNP but Ca-125 correlates with Doppler signs of volume overload, calculated using the Youden method. Carbohydrate antigen 125 appeared to increase with NT-pro-BNP, the ratio of 24 h peritoneal dialysate creatinine to serum creatinine, a decrease in albumin level, and the ECW/TBW ratio in an analysis including 489 adult patients on peritoneal dialysis [
43]. The Ca-125 serum level was measured using an immune-assay sandwich assay. There was no correlation between the Ca-125 level and 24 h urinary creatinine clearance or CRP [
43]. The researchers postulate that the observed decrease in albumin level was due to a dilution effect rather than a massive loss or cachexia. The marker has been found in peritoneal dialysate fluid and tends to increase during peritonitis not only in the PD population [
4]. This is why authors do not think that Ca-125 should be a first-row OH marker for PD populations, as it tends to increase because of the presence of dialysate fluid in the abdomen, not due to total body water imbalance. Ca-125, despite being a cancer marker, has a good chance of becoming a fluid balance indicator for patients on HD or not treated with dialysis. The marker tends to increase particularly in right heart failure due to fluid accumulation, together with stimulation during intravascular congestion and consequent damage. During our literature research, we did not find specific data confirming that Ca-125 could identify the rapid and newly developed increase in fluid accumulation in the ESKD population. Overall, results are very promising; however, correlations are not always cohesive, and more studies are needed.
The used statistical techniques to compare Ca-125 level with other OH markers (together with
p values) mentioned in the studies above are listed below in
Table 4.
As can be clearly seen from
Table 4, there are still not many studies that combine Ca-125 together with other OH markers. All the studies included NT-pro-NBP and one non-laboratory marker. In our opinion, further multi-way studies should be performed to develop the potential of Ca-125. The combination of Ca-125 together with BCM or USG could give better results in non-cancer patients than NT-pro-BNP, which is not a specific marker and tends to increase under variable conditions, which are not specifically related to OH. Natriuretic peptides increase in patients with cardiorenal syndrome even without fluid excess.
4.3. Serum Markers
- (a)
NT-pro-BNP
N-terminal pro-B type natriuretic peptide (NT-pro-BNP) is a peptide hormone synthesized mainly by ventricular cardiomyocytes in response to stretching, e.g., during the increased cardiac filling pressure, and cleared by kidneys [
51,
52]. This molecule is produced particularly by stretched ventricular and atrial cardiomyocytes [
33]. Elevated serum levels of NT-pro-BNP are observed in HF and during cardiac ischemia, pulmonary embolism, cor pulmonale, hypertension, hyperthyroidism, Cushing syndrome, hyperaldosteronism, cirrhosis, subarachnoid hemorrhage, and kidney failure. This marker also varies by sex and age and has lower values in obese patients. Its blood concentration can be affected by medications like corticosteroids, diuretics, ACE inhibitors, or thyroid hormones. Monitoring changes in NT-pro-BNP over time has been shown to be a strong diagnostic indicator, as life expectancy appears to increase as its concentration decreases [
52]. NT-pro-BNP also increases and remains significantly higher in patients with accompanying ESKD [
22,
52]. In patients with CKD, HF is a dangerous clinical issue with insufficient treatment results. This is due not only to volume overload, but also to the development of anemia. All aforementioned pathologies cause an increase in both left ventricular end-diastolic volume and mass, which eventually leads to HF [
53]. The African American Study of Kidney Disease and Hypertension enrolled patients with CKD to find an association between the risk of cardiovascular incidence and NT-pro-BNP levels in this population. It appeared that individuals with an increased plasma level of NT-pro-BNP were more likely to have cardiovascular complications, and this risk was particularly evident in patients with albuminuria [
54]. Elevated NT-pro-BNP levels indicate an increased risk of cardiovascular events in the HD population with no other signs of HF according to the study by Goto et al. This marker was an independent risk factor, as it showed no correlation with age, body mass index, blood pressure, and heart rate [
55]. Therefore, NT-pro-BNP, mainly used in cardiology, has attracted the attention of nephrologists. Its clinical application has also been discovered by nephrologists, as it tends to correlate with other OH indicators. In a meta-analysis involving 4287 patients, Schaub et al. asked whether NT-pro-BNP has a different diagnostic and prognostic utility in patients with kidney dysfunction. The correlation between GFR and natriuretic peptides was found to be statistically significant and ranged from −0.21 to −0.58, which means that during the decline in renal function, the NT-pro-BNP level increases [
56]. An elevated serum level of this peptide in patients with kidney dysfunction compared to patients with normal NT-pro-BNP confers an increased risk of mortality when compared to healthy controls [
56]. An independent relationship between eGFR and NT-pro-BNP was also observed in a study on 599 dyspneic patients with renal malfunction [
57]. Analogous results were obtained by DeFilippi et al., and one-year mortality rates were 36.3% in patients with ESKD and 19.0% in patients without ESKD [
58]. NT-pro-BNP showed a similar result in dialysis patients in a study by Park et al. [
59]. Its level was significantly higher in patients with any type of dialysis treatment compared to the control group. NT-pro-BNP also correlated with AMD, even though BMC did not detect any differences in OH status between the control and treatment groups [
59]. The marker increased together with the decrease in ejection fraction in HD patients who took part in Lee et al.’s study [
47]. NT-pro-BNP increased significantly in patients who were labeled as overhydrated by BIS. Yilmaz et al.’s study on non-dialysis dependent patients indicated that log NT-pro-BNP increased together with OH/ECW calculated by BIS and remained significantly higher in patients who were defined as overhydrated [
22]. This natriuretic peptide tends to increase in PD patients when compared to a healthy population, and scientists point out that the dialysis method has no influence on its level in the blood [
59]. NT-pro-BNP tends to increase in individuals with fluid excess during clinical studies on various methods of estimating hydration status [
22,
30,
32,
42,
43,
44,
49,
60,
61]. It was elevated during the increase in protein clearance during peritoneal dialysis [
44], associated with pleural effusion and IVC diameter [
30,
61] and ECW/TBW ratio [
32,
42,
43,
60] but not with peripheral edema [
19,
30]. It has been compared in assessments of hydration status with Ca-125; in some studies, both markers were elevated with fluid excess [
43], and in some cases, only Ca-125 increased [
62]. Núñez-Marín et al. noticed that Ca-125 but not NT-pro-BNP correlated with VEXUS indicators of OH in patients with HF [
45]. NT-pro-BNP correlated in establishing OH by BIS in Vega et al.’s study, along with a decrease in serum albumin, an increase in CRP, and proteinuria [
25]. Fluid retention in patients with ESKD calculated by BIS corresponded to an increase in NT-pro-BNP, as serum levels in hypervolemia vs. euvolemia were 4.7 times higher [
60]. In the study by Schork et al., NT-pro-BNP levels also corresponded to OH calculated using BIS in patients with ESKD [
45]. In a research study involving 179 non-dialysis CKD patients in all stages, OH measured by BCM correlated with urinary protease activity and progression of renal dysfunction, as well as with increases in NT-pro-BNP and systolic blood pressure [
42]. Schwermer et al. indicated that male gender, smoking, diabetes, and cardiovascular incidences were connected to OH [
49]. Scientists noticed also that OH induced an increase in NT-pro-BNP and troponin concentration which was interpreted as cardiovascular toxicity of water surplus. In Lee et al.’s research, OH > 1 L as calculated by BIS correlated with an elevation of NT-pro-BNP in HD patients [
47]. Similarly, in Drepper et al.’s study on PD patients, mortality was higher in those who were classified by BIS as overhydrated and with an increase in NT-pro-BNP serum level [
23]. In general, clinicians must have the knowledge that there is a long list of factors that influence NT-pro-BNP concentration, including, for example, vitamin D status in HD patients [
63].
- (b)
Adrenomedullin and proadrenomedullin
ADM is a peptide hormone synthesized by endothelial and vascular smooth muscle cells of organs like the lungs, brain, kidneys, heart, and adrenal medulla in response to an increase in fluid volume [
64,
65]. Its function is vasodilatation, preservation of endothelial integrity, and inhibition of the renin–angiotensin–aldosterone system (it protects the heart and kidneys from damage induced by angiotensin II) [
64]. It tends to decrease during the use of diuretics, blockers of the RAA system, leading to the assumption that overhydration activates the sympathetic nervous system, which stimulates its production [
64]. It has also been shown in experimental and epidemiological studies to have anti-inflammatory and antioxidant properties and the ability to reduce arterial intimal membrane hyperplasia when organs are exposed to damage [
66]. ADM is significantly elevated in HF, sepsis, and other clinical states that lead to heart malfunction. The negative correlation between the elevation of ADM and a decrease in left ventricular ejection fraction was noted by Nishikimi et al. along with a positive correlation with an increase in NYHA class and NT-pro-BNP plasma level [
67,
68]. This marker can also be used by nephrologists to investigate its correlation with hydration status, not only in patients with concomitant HF, as it shows a very promising result in cardiological research. ADM is proportionally increased with the severity of kidney disease [
67]. However, ADM is difficult to measure from a blood sample because it is rapidly removed from the circulation, and even when present in the bloodstream, it is covered by binding protein, making it inaccessible for immunometric analysis [
50,
64]. Pro-ADM is a precursor of ADM, the mid-regional fragment of which, called mid-regional ADM (MR-pro-AMD), is more stable and may directly reflect blood levels of adrenomedullin [
66,
67]. It seems to be a better predictor of 90-day mortality due to cardiac incidents than NT-pro-BNP, and its elevated level reflects poorer 12-month survival in patients with HF [
67]. In Obineche et al.’s study, ADM remained high, together with NT-pro-BNP in PD patients [
59].
It is also being studied in intensive care units among critically ill patients with septic shock and systemic inflammatory response syndrome [
68]. MR-pro-AMD also correlated with the APACHE II score, SAPS II score, IL-6, creatinine, and age. In the ENVOL study, the proadrenomedullin indicator correlated strongly positively with sodium imbalance, OH, and current SOFA score [
68]. In this study, only MR-pro-AMD and angiotensin II levels correlated significantly with sodium status, while pro-atrial natriuretic peptide (MR-pro-ANP), renin, aldosterone, cortisol, norepinephrine, epinephrine, copeptin, pro-endothelin, and EPO did not [
69]. MR-pro-AMD was also studied in HD and PD populations for up to 7 years in Austria. The majority of patients (82%) included in the study had an elevated MR-pro-AMD level ≥ 1.895 nmol/L, and this was significantly higher in subjects who passed away during the study [
70]. The peptide also correlated with another investigated marker, MR-pro-ANP, which was elevated in 99% of patients, and both parameters correlated with each other (r
2 = 0.62). The two indicators were strongly related to the probability of death due to HF, but not within the entire group of fatal and non-fatal cardiovascular disease events. ADM seems to reflect the decompensated organ’s reaction to the multifractional injuries in preserving the integrity of the cardiovascular system in ESKD. MR-pro-AMD increased not only in patients with diagnosed HF, but also with the advancement of renal disease. MR-pro-AMD tended to correlate with a relative OH status in patients with both hemodialysis and peritoneal dialysis (n = 40) in Park et al.’s study. Its growth increased with the advancement of CKD, correlating significantly with NT-pro-BNP and cardiac markers (LV mass, LV mass index, ejection fraction, and left atrial diameter) [
60]. These results give both ADM and MR-pro-ADM great potential to become independent indicators of OH.
- (c)
Galectin-3
The Gal-3 protein was discovered in the early 1980s, and since then, its role has been studied in several organs, including kidneys [
71]. In pre-clinical models, it is overexpressed in diabetic nephropathy, toxic injury, cardiorenal syndrome, or ischemia/reperfusion injury. In renal carcinoma cells, Gal-3 shows that hypoxia is crucial for its expression, and its level elevates gradually with disease stage [
72]. Gal-3 is also connected to immune-associated kidney damage like sepsis, cancer, or autoimmune diseases [
71,
73]. At the cellular level, Gal-3 is associated with renal fibrogenesis and chronic inflammation [
74,
75]. Pathomorphological analysis indicated that higher Gal-3 concentration is associated with interstitial fibrosis, tubular atrophy, and vascular intimal fibrosis. In a study on 198 patients who were treated with PD, an elevated level of Gal-3 corresponded to aortic stiffness, independently of age and gender [
76]. In a 4-year clinical trial on 280 patients with renal disease, urinary Gal-3 also correlated negatively with eGFR and positively with proteinuria [
77]. When considered as an OH marker, there is no direct connection, but the protein increases together with kidney and heart dysfunction due to overhydration. In an HF population, Gal-3 was associated with an increased risk of death after adjustment on a renal injury biomarker (
p < 0.001) [
78]. In an observational study of 1200 patients with HF, Gal-3 showed a negative correlation with eGFR, and a connection with a mortality risk when diminished renal function is present [
79]. Patients with a higher Gal-3 concentration than the established mean value (23.2 ng/mL) had a higher mortality rate. However, it had no prognostic value as a mortality risk factor when renal function was preserved. It serves not only as a renal injury marker, but also as a heart injury indicator in the ESKD population. In a population of children on HD, Gal-3 increases along with left ventricular diastolic dysfunction [
80]. The clinical guidelines announced by the American Heart Association/American College of Cardiology mentioned the utility of Gal-3 as a predictor of mortality and hospitalization in cases with HF [
80]. This property makes Gal-3 a good marker to use both in ESKD when HF is suspected and vice versa. Zhang et al. found a correlation between Gal-3 and arterial wall stiffness in HD patients. Scientists discovered that Gal-3 increased in patients with log-transformed dialysis vintage, CKD progression, and mean arterial pressure [
80]. Even if it is not a direct indicator of OH, it should be considered as a marker of renal disease due to its correlation with organ damage.
- (d)
Urocortin-2
Ucn-2 is a peptide that has a similar structure to the corticotropin-release factor and binds via its receptor CRHRH-2 [
81]. This receptor is mainly found in the central nervous system, heart, and endothelial and smooth muscle cells of the systemic vasculature. Its actions on animal tissues include vasodilation, positive inotropic and chronotropic effects, and cardioprotective abilities [
82]. An increase in Ucn-2 is seen in HF, left ventricular systolic dysfunction, non-ischemic dilated cardiomyopathy, and pulmonary arterial hypertension (PAH) [
82]. The significant adverse effect is that it can cause a significant decrease in blood pressure, leading to worsening of renal function in patients with ESKD [
82]. When its action was compared with metoprolol, it increased heart hemodynamic parameters due to its inotropic and chronotropic effects along with an increase in mean arterial pressure (MAP) [
83]. This peptide’s activity on neurohormonal and renal function is still not well understood. Ucn-2 stimulates diuresis, increases creatinine clearance, and inhibits sodium retention, but this phenomenon, which is seen in animals, is not always present in humans [
84]. Urocortin dilated renal arteries in rats, and the magnitude of this effect did not vary between animals’ genders, but it seems that the mechanism is different in females than in males [
84]. Due to its potential to become a marker of HF, Ucn-2 is still undergoing tests on both models. A study on a group of eight healthy men confirmed the hemodynamic effect, as well as the ability to decrease MAP and vascular resistance and increase the left ventricular ejection fraction [
85]. In a combined clinical and experimental study, Ucn-2 was able to decrease PAH, improve right ventricle function, and improve pulmonary circulation [
86]. However, Ucn-2 plasma levels did not differ between the patients who suffered from PAH and the healthy group, but increased m-RNA expression was observed in people with right ventricle failure. It correlated negatively with IVC collapsibility [
82]. When Ucn-2 is considered as an OH status marker or factor that can improve renal function, the results differ between studies. In a study of 12 sheep injected with mouse Ucn-2 (via a pulmonary artery catheter), there was a reduction in the effect of HF factors, as well as an improvement in renal function. It was able to decrease the MAP and left atrial pressure and suppress the production of cardiac remodeling factors (aldosterone, arginine vasopressin, and endothelin 1) [
81]. A decrease in creatinine and sodium blood levels combined with an increase in urine output indicates an improvement in renal function. The same scientific group compared the effects of Ucn-2 on heart and kidney function in a different sheep model and in comparison with dobutamine [
85]. Dobutamine and Ucn-2 improved renal function, but the significant sodium excretion was altered by Ucn-2. More interestingly, Ucn-2 decreased the overall OH status, while dobutamine increased it. It also gave better results in both HF and OH compared to the other drug. Similarl o what was found in the article mentioned above, in an animal study, Ucn-2 exhibited a better effect on diuresis, creatinine level, and sodium balance than furosemide. It was able to reduce renin, aldosterone, and vasopressin levels [
87]. Heart function also improved. Ucn-2 attenuated furosemide function, which is a promising property as some patients with ESKD develop diuretic resistance. An experimental study on rats investigating the possible influence of Ucn-2 on renal dysfunction and injury caused by ischemia or reperfusion showed that it was unable to decrease organ failure [
88]. Ucn-2 did not increase the creatinine clearance or stop anuria; a higher dose of this protein even caused a decrease in renal function. The opposite effect was observed in a human study by Chan et al., where Ucn-2 revised renal function and slashed RAA activity when compared to a placebo [
89]. The treated group required a lower dose of furosemide, and the indirect OH marker NT-pro-BNP decreased after the infusion. Ucn-2 needs further study in the future, as it has shown good results in animal models.
4.4. Non-Laboratory Tests
- (a)
Gold standard: bioimpedance spectroscopy (BIS)
BIS, as a noninvasive tool, seems to be perfect for the estimation of OH status in patients as it provides information about body composition and water placement in the body. Even though it is quite expensive, requiring an additional cost of conservation and body stickers, it is commonly used in dialysis stations and intensive care units as it is a reliable method even if the patients cannot be weighed due to their severity of illness. CKD patients who do not need renal replacement therapy also can suffer from OH. Sun et al.’s research on 302 patients with CKD stages 1–4 showed that calculated OH correlated positively with LVH [
90]. Vega et al.’s original paper showed that there is an association between OH status calculated by BIS and higher mortality in patients with ESKD stages 4–5 who are not yet undergoing kidney replacement therapy. Kaplan–Meier analysis confirmed higher mortality in patients with excessive overhydration [
25]. However, even if it is easily available and used in renal diagnosis and dialysis maintenance, it does not reflect and correspond directly with hydration status [
91,
92]. Progression towards ESKD correlates with higher OH status. This interaction was observed by Hung et al. in a nearly three-year study of patients with CKD stages 3–5. OH appeared to be a more important mortality risk factor than hypertension. Even if assumed as a gold standard, it excludes patients with limb prostheses, heart stimulation, or metal joints.
Volume status estimation is particularly significant for patients who undergo renal replacement therapy because it strongly correlates with patients’ wellbeing and mortality [
93]. Oe et al.’s study on OH measurements by BIS on patients who were treated with both PD and HD revealed that patients are prone to OH independently of the dialysis method [
94]. Another research paper, which included patients on HD, showed that OH calculated by BIS is an independent predictor of death in the dialysis population [
14]. Unfortunately, patients with metallic joint prostheses, cardiac pacemakers, decompensated cirrhosis, and limb amputations were excluded from the study due to the limitations of the BIS technique. In Kim et al.’s study on a group of 147 HD patients, OH correlated negatively with creatinine, serum albumin, white blood cell count, platelets, uric acid, potassium, phosphorus, and triglycerides [
95]. In a study by Siriopol et al. on HD patients [
29], BIS did not improve life expectancy or help maintain dry weight. In a systematic review and meta-analysis by Covic et al. on 1312 ESKD patients, BIS-based dialysis therapy did not reduce all-time mortality. Together with this observation, BIS had no effect on body change, but improved systolic blood pressure [
96]. In a study performed on peritoneal dialysis (PD) patients, BIS water balance calculations correlated with urine protein loss and higher creatinine, regardless of the duration of dialysis therapy [
44]. Comparable dependency was noticed in a pediatric population independently of the dialysis method [
32]. In a study on 13 children who underwent PD, the BIS calculations were superior to body weight measurements in assessing volume-dependent factors like blood pressure in patients with severe OH [
97]. The authors point out that the best effects are obtained when ESKD patients have regular BIS measurements, not only when OH is suspected. In a meta-analysis by Wang et al. among almost 105,000 patients who underwent both types of renal replacement therapy, one-third had overhydration detected by BIS [
12]. The estimated risk factor for mortality and cardiovascular events was ECW/TBW > 0.4. Scotland et al.’s randomized controlled trials on both HD and PD, which compared fluid management using BIS versus standard clinical methods (arterial stiffness, body weight, systolic blood pressure), estimated that spectroscopy better reflects hydration status [
98]. In a review published in 2020, the authors point out that even though BIS calculations are based on various theoretical assumptions, the effectiveness of usage in HD patients remains quite promising [
99]. However, the authors note that the noticeable benefits of BIS calculations in PD patients are limited, and further studies are needed.
In a prospective, observational study on a PD population, the association between OH and time of death or transfer to HD was clearly seen [
100].
- (b)
Ultrasonography
Ultrasonography (US) is one of the common tests performed clinically either in a specific room or beside the patient’s bed—POCUS. In terms of hydration status, doctors can visualize and measure the width of IVC, jugular veins, hepatic portal vein, and renal veins. POCUS is nowadays one of the components of physical examination inextricably connected with auscultation, palpation, and inspection [
101]. Other simple radiological examinations are inconclusive, as the presence of pleural fluid can only be observed by X-ray if at least 200 mL of fluid is present [
17]. POCUS accelerates the diagnosis or exclusion of some pathologies in real time without the need for consultation [
102]. The dependency between POCUS and hydration status can be divided according to the stages of renal disease, dialysis method, or HF.
Koratala et al. gave an example of a patient with CKD who had missed one dialysis session and suffered from shortness of breath; POCUS revealed fluid around his heart in the pericardium [
102]. Lung POCUS can reveal extravascular fluid as a diffuse B-line pattern (otherwise known as a comet). Both symptomatic and asymptomatic forms of lung congestion worsen outcomes in patients with CKD [
21]. Pulmonary congestion assessed by USG is noticeable in ESRD patients, independently of the dialysis method [
103]. Lung USG is also used by nephrologists to guide dry body weight estimation during HD [
103,
104].
In Enia et al.’s study, almost 40% of HD patients with lung congestion were asymptomatic [
105]. In the study guided by Lutradis et al., scientists studied the effect of the estimation of dry body weight based on lung USG for 8 weeks in ambulatory conditions [
106]. It appeared that patients guided by this protocol maintained dry body weight better and exhibited a decrease in blood pressure compared to a group guided by normal criteria [
106]. On the other hand, a study on 250 HD patients in whom dry body mass was adjusted using lung POCUS together with BIS did not improve life expectancy or cardiovascular events [
29]. Extracellular fluid estimated by USG also correlates with the BIS method in HD patients [
13]. Siriopol et al. concluded that both lung USG and BIS results are independently associated with all-cause mortality in an HD population, but only spectroscopy-assessed OH correlated with risk prediction for death beyond echocardiographic-based risk scores [
46]. The presence of comets, which also indicates the presence of lung fluid, was significantly decreased after the hemodialysis session and was a better overhydration predictor than BIS itself [
48]. Kaplan–Meier analysis showed that a higher mortality rate was present in patients with severe lung congestion. A limitation of lung POCUS in OH diagnosis is the fact that there is no one specific protocol available in the literature, and the fact that B-lines are not specific for pulmonary edema [
101]. As noticed and described above, the width of IVC is not always an indicator of overhydration, as its dilatation has been found in both healthy athletes and those with diseases such as valvular and pulmonary hypertension [
103]. IVC diameter is used to estimate the right atrial pressure, but it does not provide any data about the organ’s congestion [
101]. The strong limitation of the lung USG is the fact that it reflects only left heart pressure but gives no information about venous congestion [
101]. The measurements of hepatic vein flow via Doppler without a simultaneous performance of electrocardiography lead to several errors, as waveforms are influenced by heart arrhythmias [
101]. The physician’s experience also plays a key role in assessing the hydration status of the patient, which may differ in patients with obesity or hyperventilation. Misinterpretation can also be caused by improper patient positioning or the presence of a catheter [
30].
Table 5 includes different markers and whether they are sensitive, specific, or able to predict fluid imbalance. The potential cost of each test was estimated based on available prices for commercially available ELISA assays and calculated for 100 assays. Prices were checked on 31 December 2023.
When analyzing
Table 5 we can notice that Ca-125 holds great promise for male patients as the results would not be influenced by a menstrual cycle or pregnancy. When this measurement is applied to PD patients, the abdomen should be empty, and inflammation must be excluded. Unfortunately, Ca-125 concentration is affected by the presence of dialysate fluid. NT-pro-BNP seems to be the cheapest blood test but has the least specificity for the OH status itself. Its serum level is influenced by both medications widely used by ESRD patients and isolated heart dysfunction. The marker cannot differentiate between HF arising from fluid excess and that from other causes like arrhythmia. The MR-pro-ADM serum level is affected by plenty of metabolic disturbances which are widely common in the population of the 21st century. However, it holds great promise because it seems to be less altered by HF or ongoing inflammation when compared to Gal-3, Ca-125, or NT-pro-BNP. Gal-3 seems to not be a perfect marker for patients after myocardial infarction, but similarly to Ucn-2, more studies are necessary to discover its practical use. The price of Ucn-2 is the highest per 100 studies, which could be because it is not a widely used marker in daily medicine. Other modalities are often hard to calculate, but they are limited to people without obesity or pregnancy. USG results are also influenced by the doctors’ skills and eventual training.
While considering the potential synergistic use of Ca-125 with other markers, it seems to correlate best with non-laboratory tests like BIS and USG. As BIS equipment is not common in every hospital ward, we recommend the combination of blood markers together with USG. The assessment of the IVC diameter together with laboratory test confirmation could give the best and most precise results in the estimation of OH. Before the blood intake, doctors should perform a short survey for the patients, to exclude eventual errors:
- -
Is the patient pregnant?
- -
Is the patient menstruating?
- -
Is the patient suffering from HF?
- -
Is the patient suffering from liver cirrhosis or cancer or undergoing chemotherapy?
- -
Is the patient on HD or PD?