JCM | Free Full-Text | Impact of Albumin Leakage on the Mortality of Patients Receiving Hemodialysis or Online Hemodiafiltration
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1. Background
The number of patients receiving OHDF is increasing worldwide [1]. Almost half of patients receiving hemodialysis are now receiving HDF in Japan; there are now more than 120,000 patients treated with online hemodiafiltration, over 90% of whom use pre-dilution online hemodiafiltration (pre-OHDF).
In Japan, pre-OHDF is usually used because of its lower blood flow rate, requiring a rate of 200–300 mL/min, whereas post-OHDF requires more than 300 mL/min.
A high blood flow rate is unsuitable for Japanese people because of their small physique, which is why pre-OHDF is preferred.
The JRDR has compared the 1-year prognosis between patients receiving pre-OHDF and those receiving HD by using propensity score matching of the data in the national database. High-volume pre-OHDF has been associated with a reduced mortality risk and a reduced cardiovascular risk [2,3], as well as better long-term prognosis with substitution volumes of more than 40 L [2].
There have been various reports worldwide on the usefulness of OHDF. The ESHOL study showed a reduction in all-cause mortality with HDF [4].
However, in a Turkish study [5] and the Dutch CONTRAST [6], it was only useful with the high convection volume of HDF. Therefore, the mechanisms underlying HDF that may improve the long-term prognosis compared to HD are not clear.
OHDF can mainly remove a wide range of middle- to large-molecular-weight solutes that cannot be adequately removed by HD. The enhanced removal of these uremic toxins may be associated with the relief of symptoms and improved quality of life.
High-volume OHDF further increases the removal efficiency.
The removal of medium-sized solutes with a molecular weight above 17 kDa is associated with albumin leakage [7,8]. Therefore, dialysis conditions with albumin leakage imply the removal of middle- to large-molecular-weight uremic substances. In recent years, uremic toxins with larger molecular weights have been targeted [9,10], but the evidence is still lacking. In addition, there are no indicators of the removal efficiency for middle- to large-molecular-weight substances.
We hypothesized that the active removal of middle- to large-molecular-weight substances would be associated with a better prognosis. Therefore, we aimed to investigate the association between albumin leakage and prognosis in patients receiving HD and OHDF.
4. Discussion
Comparing the HD and OHDF groups, there was better long-term prognosis in the OHDF group. However, the albumin leakage was significantly higher in the OHDF group. For similar levels of albumin leakage, there was no significant difference in prognosis between the HD and OHDF groups.
The results are similar when restricted to the group of patients more than 65 years old, who are more prone to nutritional disorders.
The prognosis improved with increased albumin leakage in both the HD and OHDF groups.
The improvement in the long-term prognosis with increased albumin leakage was more pronounced in the HD group compared to the OHDF group.
The effect was more pronounced in the group with low albumin leakage and tended to diminish slightly as the albumin leakage increased.
The long-term prognosis-improving effect of albumin leakage, therefore, levels off, and further albumin leakage worsens prognosis.
Hence, it is necessary to determine the optimal amount of albumin leakage.
The prognostic benefit of the high substitution volume in OHDF compared to HD has been reported [12,13].
The relationship between the substitution volume and the prognosis was not related to the long-term prognosis with substitution volumes of more than 60 L, as albumin leakage did not increase in proportion to the substitution volume in our data.
Therefore, the prognostic improvement may be due to increased albumin leakage and a more efficient removal of middle- to large-molecular-weight substances.
In Japan, it has been noted that 33 kda of α1-microgloblin is removed with albumin leakage, and our institution has confirmed the association between albumin leakage and α1-microgloblin removal (Figure S2). This result explains why the increase in albumin leakage is associated with the removal of medium molecular weight.
And the relationship between albumin leakage and α1-microgloblin removal did not differ between HD and OHDF.
The association between albumin leakage and prognosis involves the removal of uremic toxins.
In considering uremic toxins of prognostic relevance, it is necessary to understand that there are small-molecular-weight substances, middle-molecular-weight substances in the β2-microgloblin (β2-mg) region, and middle- to large-molecular-weight substances.
It is known that the removal of small-molecular-weight substances and β2-microgloblin (β2-mg) is related to long-term prognosis [12,13,14,15].
In small-molecular-weight uremic toxins, a Kt/V of 1.4 or higher is recommended, but raising it higher does not improve the prognosis [16].
β2-Mg can be removed in hemodialysis (HD) and online hemodiafiltration (OHDF) with the evolution of the dialysis membrane. Our facility uses dialysis membranes with a β2-Mg removal rate of more than 70%, which is sufficient for removal efficiency in both HD and OHDF.
It should also be noted that there is no association between β2-Mg removal and albumin leakage. HDF can remove middle-to-large-molecular-weight substances more efficiently than HD [17].
It was recently shown that both HD and OHDF can remove β2-MG efficiently, which means that β2-MG cannot be used as a biomarker to accurately assess the removal efficiency of online HDF.
Middle molecular weight substances can be subdivided into three categories (small–middle-weight molecules of 0.5–15 kDa, medium–middle weight molecules of 15–25 kDa, and large–medium-weight molecules of 25–58 kDa) [18]. Middle- to large-molecular-weight substances are important in uremic toxins associated with albumin leakage. For example, IL-1 and IL-6 [19], parathyroid hormone, prolactin, and osteocalcin are associated with chronic inflammation and the prognosis of dialysis patients.
Recently, κ free light chains (22,000 Da) and λ free light chains (42,000 Da) have been identified as middle-molecular-weight uremic toxins [20].
The removal of middle- to large-molecular-weight substances may also be involved in the reduction in inflammatory cytokines in hemodialysis patients [20,21].
Albumin leakage is not only an indicator of the removal of middle-to-large-molecular-weight substances, but it is also related to the nutritional status, and the assessment of the nutritional status is essential for increasing albumin leakage.
Albumin production is related to energy intake and blood amino acid levels.
Patients with a good nutritional status can tolerate dialysis that leaks albumin and can benefit from the albumin leakage.
The serum albumin level is determined by the rate of synthesis in the liver, its distribution among body compartments, its catabolism, and external losses, such as during dialysis [22].
The serum albumin in hemodialysis patients has a prolonged half-life and appears to be degraded and denatured.
Hemodialysis patients have an increased albumin synthesis capacity compared to healthy subjects and need to try to maintain serum albumin levels [23].
The albumin synthesis capacity is further increased in dialysis patients when hypoalbuminemia is present [24].
Increased albumin leakage stimulates albumin synthesis and increases the mercaptoalbumin ratio [25], which also improves the albumin quality.
As albumin is synthesized in the liver, conditions such as cirrhosis also need attention.
Therefore, it is necessary to determine the albumin leakage that is acceptable for each individual patient.
There are risks and benefits of albumin leakage, and it is important to find the best balance between them.
4.1. Nutritional Status and Dietary Intake Are Related
The guidelines of the Japanese Society for Dialysis Therapy recommend an energy intake of 30–35 Kcal/kg and a protein intake of 0.9–1.2 g/kg.
However, elderly dialysis patients over 65 years of age are more likely to have nutritional problems as dietary intake declines.
Therefore, elderly dialysis patients need to increase their dietary intake to improve their nutritional status.
There was a significant positive correlation between dietary intake and albumin leakage (r = 0.21, p = 0.020).
Serum albumin is no longer a prognostic indicator because of the aggressive albumin leakage in well-nourished patient groups.
Hypoalbuminemia due to malnutrition has a poor prognosis, and albumin leakage should be minimized.
In contrast, in well-nourished patients, it may be useful to increase the albumin leakage to the maximum tolerated level.
We believe that low serum albumin levels associated with albumin leakage are not necessarily a risk factor [9].
Albumin leakage may also be involved in improved dietary intake due to leptin removal [26].
Therefore, in the long term, improved nutritional status can be expected.
However, in the short term, there is a risk of a fall in the serum albumin levels and the deterioration in the nutritional status.
Serum albumin levels should be maintained at least at 3.0–3.2 g/dL as a result of albumin leakage.
For this value, we refer to the fact that the average blood albumin level of peritoneal dialysis patients in our hospital remains around 3.1 g/dL.
Increasing dietary intake in patients over 80 years of age is a difficult problem, and in this study, the ability to tolerate albumin leakage of more than 2 g was a survival boundary.
As each patient has a different pathology, it is important to understand the patient’s condition, taking into account factors such as age, rather than just looking at blood data.
4.2. Albumin Leakage in Japanese-Style OHDF
Albumin leakage in pre-OHDF is safer than in post-HDF under the condition of high albumin leakage.
In Japan, where pre-OHDF is the main method, a wide range of membranes are used, from high albumin leakage to low albumin leakage.
In Europe, on the other hand, post-OHDF is the standard, and the membrane types are limited, with MCO and HCO membranes leaking albumin. MCO and HCO membranes have been reported to be effective in removing the middle- to large-molecular-weight uremic toxins.
However, albumin leakage in MCO membranes is limited to around 3 g [27], and HCO membranes are at risk of albumin leakage of more than 30 g.
Therefore, albumin leakage is limited in Europe. Against this background, some reports in Europe suggest that albumin leakage of around 4 g is acceptable [26].
However, Japanese-style pre-OHDF can be safely performed even when the target albumin leakage is more than 4 g.
This study showed that there are patients with albumin leakage of more than 6.5 g who have an improved prognosis, indicating that aggressive albumin leakage may be useful in some patients. It is important to determine the tolerable amount of albumin leakage based on the patient’s general condition, including nutritional status, without the aim of increasing the amount of albumin leakage.
4.3. Limitations
This study was a single-center retrospective study with a small number of cases.
However, it is also important to note that this was a single-center study, with standardized therapy selection and dialysis conditions and no facility-to-center bias. Therefore, even though the number of cases is small, it is still a meaningful study.
The presence of selection bias between HD and OHDF was considered when comparing the patient backgrounds.
Patients with hemodialysis vascular access failure or circulatory instability may be selected for HD due to the quantity of blood flow (QB) associations. Selection bias may exist in other factors as well, and this is also the case in the selection of pre-OHDF and post-OHDF. However, the current study included patients who were able to attend as outpatients and did not include patients with extremely poor nutritional status.
This was a one-point study, and subsequent changes in dialysis conditions could not be taken into account. The majority of patients had no change in dialysis method (HD or OHDF).
It is also possible that some items were propensity-score-matched according to previous reports but were not adjusted.
Albumin leakage is slightly different in every dialysis, even under the same dialysis conditions.
This is seen not only with albumin leaks but also with other uremic toxins.
The problem is that albumin leakage can only be assessed by measurement, whereas with small-molecular-weight substances, they can be assessed by Kt/v.
Of course, it also depends on factors such as the dialysis conditions, amount of replacement fluid, dialysate flow rate, dialysis membrane, size of the membrane, etc., and therefore, needs to be assessed for each condition.
The measurement method requires measuring the drainage from the dialysate, which is costly and consuming.
It is, therefore, not possible to measure it on every dialysis, and assessment with an estimated albumin leak is realistic. It is also unclear whether albumin leakage is the best marker for the removal of middle- to large-molecular-weight substances.
In addition, there are limitations in comparing patients with different albumin leakage tolerances.
The removal of uremic toxins within the tolerable range of albumin leakage is useful in biological defense, but its effectiveness also varies between individuals. There is also no way of knowing which uremic toxins are most effectively removed as middle- to large-molecular-weight substances in albumin leakage.
There is also no precise measurement to assess the balance between targets for the removal of dietary uremic toxins, uremic toxins causing chronic inflammation, inflammatory cytokines associated with chronic inflammation, etc., and the tolerated removal dose, which depends on the albumin-producing capacity. This calls for the setting of effective dialysis conditions within the tolerances of individual patients.
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