TY - JOUR
AU - Lindholm,, Bengt
AB - Abstract Hemodiafiltration (HDF) increases the removal of middle-molecular-weight uremic toxins and may improve outcomes in patients with end-stage kidney disease (ESKD), but it requires complex equipment and comes with risks associated with infusion of large volumes of substitution solution. New high-flux hemodialysis membranes with improved diffusive permeability profiles do not have these limitations and offer an attractive alternative to HDF. However, both strategies are associated with increased albumin loss into the dialysate, raising concerns about the potential for decreased serum albumin concentrations that have been associated with poor outcomes in ESKD. Many factors can contribute to hypoalbuminemia in ESKD, including protein energy wasting, inflammation, volume expansion, renal loss and loss into the dialysate; of these factors, loss into the dialysate is not necessarily the most important. Furthermore, recent studies suggest that mild hypoalbuminemia per se is not an independent predictor of increased mortality in dialysis patients, but in combination with inflammation it is a poor prognostic sign. Thus, whether hypoalbuminemia predisposes to increased morbidity and mortality may depend on the presence or absence of inflammation. In this review we summarize recent findings on the role of dialysate losses in hypoalbuminemia and the importance of concomitant inflammation on outcomes in patients with ESKD. Based on these findings, we discuss whether hypoalbuminemia may be a price worth paying for increased dialytic removal of middle-molecular-weight uremic toxins. albumin, hemodialysis, membrane permeability, middle molecules UREMIC TOXINS AND THEIR REMOVAL Not all the morbidity and mortality associated with end-stage kidney disease (ESKD) is attributable to the retention of small, water-soluble uremic toxins. In 1971, Babb et al. [1] hypothesized that there must be uremic toxins with molecular weights in the range of 500–5000 Da, so-called ‘middle molecules’. Subsequently many candidate middle-molecule–sized uremic toxins were identified, most prominently β2-microglobulin, which was shown to comprise the amyloid deposits associated with severe arthropathy in long-term hemodialysis patients [2]. With the development of more permeable membranes and improved methods for protein analysis, the range of potential uremic toxins has expanded to include proteins up to 55–60 kDa [3]. A proteomic analysis identified 333 of 2054 proteins as being abnormally abundant in plasma from patients with kidney failure [4]. In addition, some small uremic toxins effectively fall into the middle-molecule size range because they bind to larger carrier proteins [5]. Even when the abundance of a protein is normal, posttranslational modifications in the uremic environment may render it functionally abnormal and contribute to uremic toxicity. The introduction of high-flux membranes, which increased the clearance of middle-molecule-sized solutes, led to the hypothesis that some of the morbidity and mortality associated with ESKD resulted from retention of middle-molecule-sized solutes and provided the impetus for two major randomized controlled trials, the hemodialysis (HEMO) study [6], a multicenter, randomized trial in maintenance hemodialysis, and the Membrane Permeability Outcome (MPO) study [7]. Both trials randomized patients to receive hemodialysis with either low-flux or high-flux membranes, with all-cause death as the primary outcome. Neither study showed a significant survival benefit for high-flux membranes, except in a post hoc analysis for subgroups of patients. The negative results of the HEMO and MPO studies led to speculation that removal of middle-molecule-sized uremic toxins with high-flux membranes was inadequate to obtain a survival benefit. Solute transport by diffusion decreases rapidly with increasing molecular size and the ability of hemodialysis to remove middle-molecule-sized solutes is limited [8]. In contrast, sieving coefficients decrease more modestly with increasing solute size so that removal of middle-molecule-sized uremic toxins is better with convective therapies [8]. The introduction of hemodiafiltration (HDF), which combines diffusive and convective solute removal, allowed examination of the possibility that the negative findings of the HEMO and MPO studies reflected inadequate removal of middle-molecule-sized solutes with high-flux hemodialysis. Four randomized controlled trials of HDF have been conducted with mixed results [9–12]. Three trials found no survival advantage for patients treated with HDF compared with low-flux [9] or high-flux [10, 12] hemodialysis, while the fourth found significantly better survival for patients treated with HDF compared with patients predominantly treated with high-flux hemodialysis [11]. For three of the trials, post hoc analyses showed that higher convection volumes were associated with better survival. These findings were supported by an analysis of individual patient data for all 2793 patients who participated in the four trials that showed the largest survival benefit was obtained for convection volumes >23 L/1.73 m2 body surface area [13]. Taken together, these observations support the hypothesis that middle-molecule-sized uremic toxins contribute to morbidity and mortality associated with ESKD and suggest that their removal by hemodialysis, as it is currently practiced, is insufficient to mitigate this toxicity. Although not definitive [14], the evidence to date suggests a possible role for HDF with convection volumes >20 L in improving patient outcomes. However, even if a benefit of high-volume HDF was confirmed by future studies, it remains uncertain that such high convection volumes can be routinely delivered. The convection volume in postdilution HDF is limited by the filtration fraction, which generally cannot exceed 30% [15], making it difficult to achieve a high convection volume with thrice-weekly 4-h treatments for patients with a large body surface area, even with blood flow rates >400 mL/min. Increasing the frequency or duration of treatment could overcome that limitation but can be difficult to implement for cost and logistical reasons. HEMODIALYZER MEMBRANES Most currently used dialyzers fall into one of two categories, low flux or high flux, based on their removal of middle-molecule-sized uremic toxins (Table 1). Removal of those solutes is negligible with low-flux membranes [16]. While there is some removal with high-flux membranes, it appears insufficient to provide a survival benefit. The performance of high-flux membranes can be enhanced by the addition of convection, as in HDF; however, optimal clearance of higher molecular weight solutes depends on both patient-specific (blood access, hematocrit) and operational (blood flow rate, treatment time, ultrafiltration rate) factors and can be difficult to achieve in some patients. Membranes are becoming available that address those difficulties by refining the permeability–molecular weight characteristics of the membrane to enhance removal of higher molecular weight solutes that accumulate in ESKD patients, such as cytokines and free light chains, without the superimposed convection and infusion of substitution solution associated with HDF [22]. These new membranes, which do not require the online preparation and infusion of the large volumes of substitution fluid needed for HDF, are variously referred to as medium cutoff (MCO) [17, 18, 23], high cutoff (HCO) [20, 21, 24] and protein permeable [19]. Other poorly defined terms, such as super-flux and super high-flux, have also been used. These new membranes differ from traditional high-flux membranes in that they allow varying amounts of albumin loss into the dialysate (Table 1). Table 1 Classification of hemodialysis membranes Category Ultrafiltration coefficienta (mL/h/mmHg/m2) β2-microglobulin clearanceb (mL/min) Albumin lossc (g) Sieving coefficienta Reference β2-microglobulin Albumin Low flux <12 <10 0 – 0 [16] High flux 14–40 20–40 <0.5 0.7–0.8 <0.01 [6] MCO 40–60 >80 2–4 0.99 <0.01 [17, 18] Protein leaking >40 >80 2–6 0.9–1.0 0.01–0.03 [19] HCO 40–60 – 9–23 1.0 <0.2 [20, 21] Category Ultrafiltration coefficienta (mL/h/mmHg/m2) β2-microglobulin clearanceb (mL/min) Albumin lossc (g) Sieving coefficienta Reference β2-microglobulin Albumin Low flux <12 <10 0 – 0 [16] High flux 14–40 20–40 <0.5 0.7–0.8 <0.01 [6] MCO 40–60 >80 2–4 0.99 <0.01 [17, 18] Protein leaking >40 >80 2–6 0.9–1.0 0.01–0.03 [19] HCO 40–60 – 9–23 1.0 <0.2 [20, 21] a In vitro. b For conventional hemodialysis with a blood flow rate of 300–400 mL/min. Includes removal by diffusion, convection and adsorption. c For 4 h of conventional hemodialysis. View Large Table 1 Classification of hemodialysis membranes Category Ultrafiltration coefficienta (mL/h/mmHg/m2) β2-microglobulin clearanceb (mL/min) Albumin lossc (g) Sieving coefficienta Reference β2-microglobulin Albumin Low flux <12 <10 0 – 0 [16] High flux 14–40 20–40 <0.5 0.7–0.8 <0.01 [6] MCO 40–60 >80 2–4 0.99 <0.01 [17, 18] Protein leaking >40 >80 2–6 0.9–1.0 0.01–0.03 [19] HCO 40–60 – 9–23 1.0 <0.2 [20, 21] Category Ultrafiltration coefficienta (mL/h/mmHg/m2) β2-microglobulin clearanceb (mL/min) Albumin lossc (g) Sieving coefficienta Reference β2-microglobulin Albumin Low flux <12 <10 0 – 0 [16] High flux 14–40 20–40 <0.5 0.7–0.8 <0.01 [6] MCO 40–60 >80 2–4 0.99 <0.01 [17, 18] Protein leaking >40 >80 2–6 0.9–1.0 0.01–0.03 [19] HCO 40–60 – 9–23 1.0 <0.2 [20, 21] a In vitro. b For conventional hemodialysis with a blood flow rate of 300–400 mL/min. Includes removal by diffusion, convection and adsorption. c For 4 h of conventional hemodialysis. View Large One concern with therapies that increase large solute removal is that substances essential to patient health are also removed. Of particular concern is albumin loss, given that albumin is the principal determinant of the colloid pressure of plasma, and the repeated observation that hypoalbuminemia is associated with poor outcomes in patients treated with hemodialysis [25, 26] or peritoneal dialysis [27]. Thus, if therapies that increase large solute removal at the expense of albumin loss predispose to hypoalbuminemia, how much albumin must be lost for that to occur and does the occurrence of hypoalbuminemia compromise patient outcomes are important questions. ALBUMIN HOMEOSTASIS AND ESKD Albumin is the most abundant protein in plasma, accounting for about half the protein mass (Figure 1). Because of its molecular weight (66.5 kDa)—which allows most of it to remain in plasma—and its ability to hold sodium ions through a Gibbs–Donnan interaction, albumin is the principal determinant of plasma colloid pressure [28]. Albumin is also an important carrier protein for many substances, including bilirubin, long-chain fatty acids, divalent cations and drugs, and its reduced sulfhydryl groups comprise the major antioxidant in plasma [28]. FIGURE 1 View largeDownload slide Relative abundance of plasma proteins. The upper right-hand quadrant of the pie chart represents the proteins listed in the table. *Cutoff of the kidney filtration apparatus. **Usual cutoff of high-flux dialysis membranes. FIGURE 1 View largeDownload slide Relative abundance of plasma proteins. The upper right-hand quadrant of the pie chart represents the proteins listed in the table. *Cutoff of the kidney filtration apparatus. **Usual cutoff of high-flux dialysis membranes. Serum albumin concentration is determined by albumin synthesis rate, catabolism (fractional catabolic rate), distribution between intra- and extravascular compartments and external losses (Figure 2). Healthy adults have ∼120 g of albumin in their circulation and an even larger pool of ∼180 g in their extravascular space [29]. Albumin is synthesized by hepatocytes at ∼10.5 g/day [28, 30, 31]. Downregulation of albumin mRNA in the liver with a consequent reduction in albumin synthesis can occur with inflammation, alone or in the presence of protein-energy wasting [32–34]. FIGURE 2 View largeDownload slide Albumin homeostasis in healthy individuals and in ESKD. The transcapillary escape rate of albumin was 13.7 ± 8.9 (%/h) in patients on peritoneal dialysis and 8.22 ± 5.8 (%/h) in non-uraemic subjects [51]. FIGURE 2 View largeDownload slide Albumin homeostasis in healthy individuals and in ESKD. The transcapillary escape rate of albumin was 13.7 ± 8.9 (%/h) in patients on peritoneal dialysis and 8.22 ± 5.8 (%/h) in non-uraemic subjects [51]. Albumin removal is a first-order process wherein catabolism decreases in states of hypoalbuminemia [32]. Also, increased loss of albumin in disordered states is usually accompanied by an increase in albumin synthesis [35], although that increase may be insufficient to prevent hypoalbuminemia if the increased albumin loss is accompanied by an increase in catabolic rate, as occurs in the nephrotic syndrome [35]. In patients with residual renal function, transcapillary escape from plasma to extravascular compartments, and not renal excretion, is the major determinant of plasma albumin clearance [36]. In anuric patients undergoing hemodialysis with currently used membranes, the extracorporeal loss of albumin during dialysis is likely to be lower than the transcapillary escape rate. EXTERNAL ALBUMIN LOSS IN ESKD AND ITS IMPACT ON SERUM ALBUMIN Albumin synthesis is thought to be unimpaired in patients with ESKD in the absence of comorbid conditions, such as chronic inflammation [30]. However, albumin loss through normal catabolic pathways may be augmented by loss through processes related to dialysis, such as loss into the dialysate in peritoneal dialysis [30, 37], and loss into the dialysate and by membrane adsorption in high-flux hemodialysis and HDF [38]. Patients with nephrotic syndrome can experience significant urinary albumin loss in the range of 25–80 g/week, leading to plasma albumin concentrations of ≤25 g/L [35, 39], because albumin synthesis, although increased, cannot compensate for urinary loss of albumin [39]. Continuous ambulatory peritoneal dialysis (CAPD) patients experience similar levels of albumin loss into the peritoneal dialysate (30–40 g/week) [30, 37]. However, their serum albumin concentrations are nearly normal (35 ± 5 g/L) [40, 41]. Indeed, Kaysen et al. [30] showed no difference in plasma and total albumin mass between healthy individuals and CAPD patients, suggesting that serum albumin concentrations in CAPD patients would be in the normal range if volume expansion was considered. The reasons for the difference in serum albumin concentration for the same level of albumin loss between CAPD patients and patients with nephrotic syndrome are not clear. The observation that there is a good correlation between albumin loss and serum albumin concentration in CAPD patients, but not in patients with nephrotic syndrome [30], supports more complex kinetics in the latter group, including additional albumin loss secondary to renal catabolism, potentially limiting the application of those data to dialysis patients. There can be marked differences between the consequences of renal losses of albumin and losses of albumin through nonglomerular routes, such as can occur with CAPD or HDF. For example, angiopoietin-like 4 protein release from podocytes leads to hyperlipidemia in nephrotic syndrome [42], and this would not occur if albumin was lost through a nonglomerular route. However, regardless of the route of albumin loss, increased albumin synthesis would be accompanied by increased hepatic synthesis of other proteins, including fibrinogen, which might increase thrombotic risk [43, 44]. As discussed above, albumin losses in peritoneal dialysis patients can be as high as ≥30–40 g/week, or ∼35–45% of the normal albumin turnover rate. Despite this marked increase in the effective catabolic rate, serum albumin concentrations generally remain in the lower half of the normal range, reflecting a normal ability to increase albumin synthesis and/or decrease albumin catabolism [30]. Indeed, in hemodialysis patients with a normal nutritional status and without signs of inflammation, there is a 30–35% increase in the basal rate of albumin synthesis [45]. For many patients, the tendency for serum albumin levels to be slightly low may reflect volume expansion [46] or changes in gastrointestinal removal rather than reduced synthesis or increased catabolism. More marked hypoalbuminemia may reflect an inability to compensate for increased albumin loss secondary to chronic inflammation [45, 47, 48], reduced dietary protein intake [49], residual albuminuria [47] or a combination of these factors. SERUM ALBUMIN AND OUTCOMES Although a low serum albumin concentration has been associated with a poor outcome in ESKD [25–27], the reasons for such a relationship are less clear. The serum albumin concentration threshold at which the risk of death increased was 2–4 g/L lower for peritoneal dialysis than for hemodialysis patients, suggesting that this threshold varies by dialysis modality [27]. One explanation for the difference could be that albumin is a negative acute-phase reactant, such that a low serum albumin may be an indicator of underlying inflammation rather than an inherent inability to adequately synthesize albumin to match albumin loss through catabolic or dialysis-specific mechanisms. Mortality risk was found to be increased in patients with low serum albumin and high C-reactive protein (CRP) but not increased in patients with low serum albumin and normal CRP [50]. Also, albumin synthesis relies on the availability of dietary protein [39]. Thus hypoalbuminemia may be an indicator of underlying processes such as inflammation [47, 48, 51], renal losses [47], protein energy wasting or fluid overload, which predispose to a poor outcome rather than being the cause of that outcome. Additional loss of albumin associated with the use of a protein-permeable membrane may not necessarily exacerbate that situation. Interestingly, dialysis treatment modalities that are associated with improved outcomes (larger membrane surface, larger pore size, high convective volumes, higher transmembrane pressure, postdilution) [52] are also associated with increased albumin loss into the dialysate [53]. The extent to which the increased albumin loss associated with renal replacement therapies results in hypoalbuminemia and if this predisposes to the adverse outcomes associated with hypoalbuminemia are clearly important questions when contemplating the introduction of more permeable membranes. Very little albumin is lost into the dialysate with conventional hemodialysis. Albumin loss with HDF is greater, with amounts in the range of 0.5–4.2 g being reported for postdilution HDF with the most widely used high-flux dialyzers [54, 55]. On a weekly basis, those levels are comparable to what is excreted in urine by macroalbuminuric patients with type 1 diabetes (median 1303 mg/day) [56] but far higher than albumin excretion (median 7.2 mg/day) among the general population [57]. However, reports of albumin loss into the dialysate for HDF are generally from a single treatment and few studies address the question of whether or not a sustained loss of that amount of albumin over time has a significant impact on serum albumin levels. That this level of albumin loss does not pose a risk is suggested by the results of four randomized clinical trials in which HDF was performed using dialyzers comparable to those used in the single-treatment studies. In those four randomized clinical trials, serum albumin concentrations in the HDF-treated group did not differ [9, 11, 12] or were only slightly lower [10] than in the hemodialysis-treated group. Indeed, the serum albumin concentrations approached those in healthy individuals, particularly if allowance is made for predialysis volume expansion. Higher levels of albumin loss can occur in situations such as continuous ambulatory peritoneal dialysis (CAPD) and continuous cycling peritoneal dialysis (CCPD) [58, 59] and, in extreme cases, hemodialysis [59–61]. For example, Kaplan measured albumin losses into dialysate of up to 20 g/treatment in patients undergoing hemodialysis with reused dialyzers containing polysulfone membranes where the permeability of the membranes was increased by cleaning with bleach between successive treatments [60]. Despite an average albumin loss on the order of 20–30 g/week, serum albumin concentrations (35.5 ± 0.1 g/L) were similar to those reported for CAPD patients [41]. Table 2 summarizes changes in serum albumin concentrations in studies of at least 10 weeks during which time there was a high level of albumin loss into the dialysate. Taken together, those data suggest that in the absence of significant inflammation, patients treated thrice weekly with therapies that result in an albumin loss of ∼>20 g/week experience a decrease of ∼10% in serum albumin concentration. However, it is not clear that this modest decrease adversely impacts outcomes in the absence of comorbid conditions associated with inflammation. Hypoalbuminemia and/or the magnitude of albumin loss into the dialysate are not independent predictors of reduced survival in peritoneal dialysis patients [62, 63], and patients treated by HDF with the highest convection volumes, which would produce the greatest loss of albumin into the dialysate, have superior outcomes compared with patients treated with hemodialysis or HDF with relatively low convection volumes [11, 13]. Table 2 Albumin loss reported in studies of at least 10-weeks duration and the impact on serum albumin Therapy Albumin loss (g/week) Serum albumin (g/L) Time (months) Albumin loss associated with decreased serum albumin n Reference PD 27 ± 2 38 ± 1 37 ± 4.4 Yes 27 [58] PD 20 ± 8* 37 ± 2 24 No 7 [40] PD 30 ± 8* 39 ± 7 24 No 10 [40] PD 19 ± 4 35 ± 4 12 No 12 [59] HD 24–36 36 ± 1 2.5 Yes 11 [60] HD 23 ± 7 32 ± 3 36 Yes 118 [61] HD 22 ± 4 36 ± 6 12 Yes 12 [59] Therapy Albumin loss (g/week) Serum albumin (g/L) Time (months) Albumin loss associated with decreased serum albumin n Reference PD 27 ± 2 38 ± 1 37 ± 4.4 Yes 27 [58] PD 20 ± 8* 37 ± 2 24 No 7 [40] PD 30 ± 8* 39 ± 7 24 No 10 [40] PD 19 ± 4 35 ± 4 12 No 12 [59] HD 24–36 36 ± 1 2.5 Yes 11 [60] HD 23 ± 7 32 ± 3 36 Yes 118 [61] HD 22 ± 4 36 ± 6 12 Yes 12 [59] * Estimated albumin loss in patients with reduction of serum albumin greater than (n = 7) or less than (n = 10) 10% after 24 months on PD. HD, hemodialysis; PD, peritoneal dialysis. View Large Table 2 Albumin loss reported in studies of at least 10-weeks duration and the impact on serum albumin Therapy Albumin loss (g/week) Serum albumin (g/L) Time (months) Albumin loss associated with decreased serum albumin n Reference PD 27 ± 2 38 ± 1 37 ± 4.4 Yes 27 [58] PD 20 ± 8* 37 ± 2 24 No 7 [40] PD 30 ± 8* 39 ± 7 24 No 10 [40] PD 19 ± 4 35 ± 4 12 No 12 [59] HD 24–36 36 ± 1 2.5 Yes 11 [60] HD 23 ± 7 32 ± 3 36 Yes 118 [61] HD 22 ± 4 36 ± 6 12 Yes 12 [59] Therapy Albumin loss (g/week) Serum albumin (g/L) Time (months) Albumin loss associated with decreased serum albumin n Reference PD 27 ± 2 38 ± 1 37 ± 4.4 Yes 27 [58] PD 20 ± 8* 37 ± 2 24 No 7 [40] PD 30 ± 8* 39 ± 7 24 No 10 [40] PD 19 ± 4 35 ± 4 12 No 12 [59] HD 24–36 36 ± 1 2.5 Yes 11 [60] HD 23 ± 7 32 ± 3 36 Yes 118 [61] HD 22 ± 4 36 ± 6 12 Yes 12 [59] * Estimated albumin loss in patients with reduction of serum albumin greater than (n = 7) or less than (n = 10) 10% after 24 months on PD. HD, hemodialysis; PD, peritoneal dialysis. View Large As mentioned above, increased albumin loss also raises the possibility of mimicking the hypercoagulable state and hyperlipidemia that occurs in patients with nephrotic syndrome [43, 44]. However, the classic pathophysiologic mechanism of increased production of lipoproteins and fibrinogen in response to hypoalbuminemia in nephrotic syndrome is complex [42] and may not occur if albumin is lost through a nonglomerular route. Although the concern is that albumin loss may be harmful to patients treated with therapies that leak albumin into the dialysate, it could be argued that such albumin loss might be beneficial. Albumin is the major carrier protein for several small protein-bound uremic toxins associated with endothelial dysfunction [64, 65] and cardiovascular events [66]. Those protein-bound toxins are poorly removed by conventional hemodialysis [67], and allowing some albumin loss into the dialysate may substantially increase their removal [68]. Moreover, plasma albumin is subject to irreversible posttranslational modifications, including oxidation, glycosylation and carbamylation. Those processes are more pronounced in the uremic environment [69–71] and have been linked to adverse outcomes in ESKD patients [70, 72, 73]. Modified forms of albumin are preferentially cleared by renal excretion [74] and some albumin loss into the dialysate may help offset the loss of that pathway. The potential benefit of allowing some albumin leakage into the dialysate, and stimulation of increased hepatic synthesis of functional unmodified albumin, is one of the factors underlying the development and use of high-performance, protein-leaking membranes in Japan. In one observational study with a membrane that leaked 7.7 ± 1.0 g of albumin per treatment, 118 patients followed for 3 years had a decrease of ∼6% in serum albumin concentration but significantly fewer hospitalizations and other complications than 314 patients treated with conventional hemodialysis membranes [61]. In a second study of 690 patients followed for 7 years, treatment with dialyzers allowing an albumin loss of >3 g/treatment was associated with a significantly lower mortality than treatment with dialyzers limiting albumin loss to <3 g/treatment [75]. CONCLUSION There is increasing evidence that enhanced removal of middle-molecule-weight solutes improves outcomes in ESKD patients. Currently HDF provides the best removal of those solutes; however, HDF requires more complex equipment and comes with the risks associated with infusion of large volumes of substitution solution prepared online. New membranes with improved permeability profiles are becoming available that offer an alternative to HDF. Some of these new membranes are associated with albumin loss into the dialysate, raising concerns about their potential to decrease serum albumin concentrations. Available data suggest a need for caution when contemplating routine use of dialyzers containing membranes that produce a loss of ≥20 g/week of albumin, whereas the use of dialyzers resulting in a weekly loss of ≤12 g appears to pose little risk to patients. On that basis, high-flux membranes able to remove an expanded range of middle-molecule-weight uremic toxins, but with limited albumin loss, could provide a useful alternative to online HDF without the need for specialized equipment and the risks associated with the infusion of large volumes of substitution solution. Further studies are needed to address the hypothesis that losing some albumin might be beneficial due to the removal of albumin-bound toxins and modified forms of albumin that have lost their antioxidant properties. FUNDING Baxter Novum is the result of a grant from Baxter Healthcare Corporation to Karolinska Institutet. CONFLICT OF INTEREST STATEMENT R.A.W. has been a consultant to Baxter Healthcare and reports personal fees from Baxter Healthcare outside the submitted work. W.B., A.A.B. and B.L. are employees of Baxter Healthcare. P.S. has been a member of Baxter advisory boards, lectured at scientific meetings arranged by Baxter Healthcare and reports personal fees from Baxter during the conduct of the study; grants and personal fees from AstraZeneca and personal fees from Corvídia, Akeiba, Reata and Pfizer, outside the submitted work. F.C.A. declares no conflict of interest. REFERENCES 1 Babb AL , Popovich RP , Christopher TG et al. The genesis of the square meter-hour hypothesis . Trans Am Soc Artif Intern Organs 1971 ; 17 : 81 – 91 Google Scholar PubMed 2 Gejyo F , Odani S , Yamada T et al. Beta 2-microglobulin: a new form of amyloid protein associated with chronic hemodialysis . Kidney Int 1986 ; 30 : 385 – 390 Google Scholar Crossref Search ADS PubMed 3 Chmielewski M , Cohen G , Wiecek A et al. The peptidic middle molecules: is molecular weight doing the trick? Semin Nephrol 2014 ; 34 : 118 – 134 Google Scholar Crossref Search ADS PubMed 4 Glorieux G , Mullen W , Duranton F et al. New insights in molecular mechanisms involved in chronic kidney disease using high-resolution plasma proteome analysis . Nephrol Dial Transplant 2015 ; 30 : 1842 – 1852 Google Scholar Crossref Search ADS PubMed 5 Vanholder R , Schepers E , Pletinck A et al. An update on protein-bound uremic retention solutes . J Ren Nutr 2012 ; 22 : 90 – 94 Google Scholar Crossref Search ADS PubMed 6 Eknoyan G , Beck GJ , Cheung AK et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis . N Engl J Med 2002 ; 347 : 2010 – 2019 Google Scholar Crossref Search ADS PubMed 7 Locatelli F , Martin-Malo A , Hannedouche T et al. Effect of membrane permeability on survival of hemodialysis patients . J Am Soc Nephrol 2009 ; 20 : 645 – 654 Google Scholar Crossref Search ADS PubMed 8 Eloot S , Ledebo I , Ward RA. Extracorporeal removal of uremic toxins: can we still do better? Semin Nephrol 2014 ; 34 : 209 – 227 Google Scholar Crossref Search ADS PubMed 9 Grooteman MP , van den Dorpel MA , Bots ML et al. Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes . J Am Soc Nephrol 2012 ; 23 : 1087 – 1096 Google Scholar Crossref Search ADS PubMed 10 Ok E , Asci G , Toz H et al. Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study . Nephrol Dial Transplant 2013 ; 28 : 192 – 202 Google Scholar Crossref Search ADS PubMed 11 Maduell F , Moreso F , Pons M et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients . J Am Soc Nephrol 2013 ; 24 : 487 – 497 Google Scholar Crossref Search ADS PubMed 12 Morena M , Jaussent A , Chalabi L et al. Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly . Kidney Int 2017 ; 91 : 1495 – 1509 Google Scholar Crossref Search ADS PubMed 13 Peters SA , Bots ML , Canaud B et al. Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials . Nephrol Dial Transplant 2016 ; 31 : 978 – 984 Google Scholar Crossref Search ADS PubMed 14 Marshall MR. Measuring the patient response to dialysis therapy: hemodiafiltration and clinical trials . Kidney Int 2017 ; 91 : 1279 – 1282 Google Scholar Crossref Search ADS PubMed 15 Tattersall JE , Ward RA , Canaud B et al. Online haemodiafiltration: definition, dose quantification and safety revisited . Nephrol Dial Transplant 2013 ; 28 : 542 – 550 Google Scholar Crossref Search ADS PubMed 16 Cheung AK , Levin NW , Greene T et al. Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study . J Am Soc Nephrol 2003 ; 14 : 3251 – 3263 Google Scholar Crossref Search ADS PubMed 17 Kirsch AH , Lyko R , Nilsson LG et al. Performance of hemodialysis with novel medium cut-off dialyzers . Nephrol Dial Transplant 2017 ; 32 : 165 – 172 Google Scholar PubMed 18 Hulko M , Speidel R , Gauss J et al. In vitro benchmark of cytokine removal by dialyzers with various permeability profiles . Int J Artif Organs 2017 ; 40 : 615 – 621 Google Scholar Crossref Search ADS PubMed 19 Ward RA. Protein-leaking membranes for hemodialysis: a new class of membranes in search of an application? J Am Soc Nephrol 2005 ; 16 : 2421 – 2430 Google Scholar Crossref Search ADS PubMed 20 Boschetti-de-Fierro A , Voigt M , Storr M et al. Extended characterization of a new class of membranes for blood purification: the high cut-off membranes . Int J Artif Organs 2013 ; 36 : 455 – 463 Google Scholar Crossref Search ADS PubMed 21 Boschetti-de-Fierro A , Voigt M , Storr M et al. MCO membranes: enhanced selectivity in high-flux class . Sci Rep 2015 ; 5 : 18448 Google Scholar Crossref Search ADS PubMed 22 Ronco C. The rise of expanded hemodialysis . Blood Purif 2017 ; 44 : I – VIII Google Scholar Crossref Search ADS 23 Zweigart C , Boschetti-de-Fierro A , Hulko M et al. Medium cut-off membranes–closer to the natural kidney removal function . Int J Artif Organs 2017 ; 40 : 328 – 334 Google Scholar Crossref Search ADS PubMed 24 Kneis C , Beck W , Boenisch O et al. Elimination of middle-sized uremic solutes with high-flux and high-cut-off membranes: a randomized in vivo study . Blood Purif 2013 ; 36 : 287 – 294 Google Scholar Crossref Search ADS PubMed 25 Owen WF , Lew NL , Liu Y et al. The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis . N Engl J Med 1993 ; 329 : 1001 – 1006 Google Scholar Crossref Search ADS PubMed 26 Foley RN , Parfrey PS , Harnett JD et al. Hypoalbuminemia, cardiac morbidity, and mortality in end-stage renal disease . J Am Soc Nephrol 1996 ; 7 : 728 – 736 Google Scholar PubMed 27 Mehrotra R , Duong U , Jiwakanon S et al. Serum albumin as a predictor of mortality in peritoneal dialysis: comparisons with hemodialysis . Am J Kidney Dis 2011 ; 58 : 418 – 428 Google Scholar Crossref Search ADS PubMed 28 Levitt DG , Levitt MD. Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements . Int J Gen Med 2016 ; 9: 229 – 255 29 Kragh-Hansen U , Minchiotti L , Galliano M et al. Human serum albumin isoforms: genetic and molecular aspects and functional consequences . Biochim Biophys Acta 2013 ; 1830 : 5405 – 5417 Google Scholar Crossref Search ADS PubMed 30 Kaysen GA , Schoenfeld PY. Albumin homeostasis in patients undergoing continuous ambulatory peritoneal dialysis . Kidney Int 1984 ; 25 : 107 – 114 Google Scholar Crossref Search ADS PubMed 31 Ballmer PE , McNurlan MA , Milne E et al. Measurement of albumin synthesis in humans: a new approach employing stable isotopes . Am J Physiol 1990 ; 259 : E797 – E803 Google Scholar PubMed 32 Kaysen GA. Biological basis of hypoalbuminemia in ESRD . J Am Soc Nephrol 1998 ; 9 : 2368 – 2376 Google Scholar PubMed 33 Kaysen GA , Dubin JA , Müller HG et al. Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients . Kidney Int 2002 ; 61 : 2240 – 2249 Google Scholar Crossref Search ADS PubMed 34 Friedman AN , Fadem SZ. Reassessment of albumin as a nutritional marker in kidney disease . J Am Soc Nephrol 2010 ; 21 : 223 – 230 Google Scholar Crossref Search ADS PubMed 35 Jensen H , Rossing N , Andersen SB et al. Albumin metabolism in the nephrotic syndrome in adults . Clin Sci 1967 ; 33 : 445 – 457 Google Scholar PubMed 36 Öberg CM , Rippe B. Can early plasma elimination rate be used to quantify renal clearance of macromolecules? Am J Physiol 2015 ; 308 : F164 – F165 Google Scholar Crossref Search ADS 37 Nolph KD , Moore HL , Prowant B et al. Continuous ambulatory peritoneal dialysis with a high flux membrane . ASAIO J 1993 ; 39 : 904 – 909 Google Scholar Crossref Search ADS PubMed 38 Yamashita AC. Mass transfer mechanisms in high-performance membrane dialyzers . Contrib Nephrol 2011 ; 173 : 95 – 102 Google Scholar Crossref Search ADS PubMed 39 Kaysen GA , Gambertoglio J , Jimenez I et al. Effect of dietary protein intake on albumin homeostasis in nephrotic patients . Kidney Int 1986 ; 29 : 572 – 577 Google Scholar Crossref Search ADS PubMed 40 Caravaca F , Arrobas M , Dominguez C. Serum albumin and other serum protein fractions in stable patients on peritoneal dialysis . Perit Dial Int 2000 ; 20 : 703 – 707 Google Scholar PubMed 41 Flanigan MJ , Rocco MV , Prowant B et al. Clinical performance measures: the changing status of peritoneal dialysis . Kidney Int 2001 ; 60 : 2377 – 2384 Google Scholar Crossref Search ADS PubMed 42 Clement LC , Macé C , Avila-Casado C et al. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome . Nat Med 2014 ; 20 : 37 – 46 Google Scholar Crossref Search ADS PubMed 43 de Sain-van der Velden MGM , Kaysen GA , de Meer K et al. Proportionate increase in fibrinogen and albumin synthesis in nephrotic patients: measurement with stable isotopes . Kidney Int 1998 ; 53 : 181 – 188 Google Scholar Crossref Search ADS PubMed 44 Vaziri ND. Molecular mechanisms of lipid disorders in nephrotic syndrome . Kidney Int 2003 ; 63 : 1964 – 1976 Google Scholar Crossref Search ADS PubMed 45 Kaysen GA , Rathore V , Shearer GC et al. Mechanisms of hypoalbuminemia in hemodialysis patients . Kidney Int 1995 ; 48 : 510 – 516 Google Scholar Crossref Search ADS PubMed 46 Cigarran S , Barril G , Cirugeda A et al. Hypoalbuminemia is also a marker of fluid excess determined by bioelectrical impedance parameters in dialysis patients . Therapher Dial 2007 ; 11 : 114 – 120 Google Scholar Crossref Search ADS 47 Gama-Axelsson T , Heimbürger O , Stenvinkel P et al. Serum albumin as predictor of nutritional status in patients with ESRD . Clin J Am Soc Nephrol 2012 ; 7 : 1446 – 1453 Google Scholar Crossref Search ADS PubMed 48 Kaysen GA , Dubin JA , Müller HG et al. Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients . Kidney Int 2004 ; 65 : 1408 – 1415 Google Scholar Crossref Search ADS PubMed 49 Rothschild MA , Oratz M , Schreiber SS. Regulation of albumin metabolism . Annu Rev Med 1975 ; 26 : 91 – 104 Google Scholar Crossref Search ADS PubMed 50 Alves FC , Sun J , Qureshi AR et al. The higher mortality associated with low serum albumin is dependent on systemic inflammation in end stage kidney disease . PLoS One 2018 ; 13 : e0190410 Google Scholar Crossref Search ADS PubMed 51 Yu Z , Tan BK , Dainty S et al. Hypoalbuminaemia, systemic albumin leak and endothelial dysfunction in peritoneal dialysis patients . Nephrol Dial Transplant 2012 ; 27 : 4437 – 4445 Google Scholar Crossref Search ADS PubMed 52 Canaud B , Morena M , Leray-Moragues H et al. Overview of clinical studies in hemodiafiltration: what do we need now? Hemodial Int 2006 ; 10 ( Suppl 1 ): S5 – S12 Google Scholar Crossref Search ADS PubMed 53 Santoro A , Canova C , Mancini E et al. Protein loss in on-line hemofiltration . Blood Purif 2004 ; 22 : 261 – 268 Google Scholar Crossref Search ADS PubMed 54 Samtleben W , Dengler C , Reinhardt B et al. Comparison of the new polyethersulfone high-flux membrane DIAPES HF800 with conventional high-flux membranes during on-line haemodiafiltration . Nephrol Dial Transplant 2003 ; 18 : 2382 – 2386 Google Scholar Crossref Search ADS PubMed 55 Maduell F , Arias-Guillen M , Fontseré N et al. Elimination of large uremic toxins by a dialyzer specifically designed for high-volume convective therapies . Blood Purif 2014 ; 37 : 125 – 130 Google Scholar Crossref Search ADS PubMed 56 Osicka TM , Houlihan CA , Chan JG et al. Albuminuria in patients with Type 1 diabetes is directly linked to changes in the lysosome-mediated degradation of albumin during renal passage . Diabetes 2000 ; 49 : 1579 – 1584 Google Scholar Crossref Search ADS PubMed 57 Abdelmalek JA , Gansevoort RT , Lambers Heerspink HJ et al. Estimated albumin excretion rate versus urine albumin-creatinine ratio for the assessment of albuminuria: a diagnostic test study from the Prevention of Renal and Vascular Endstage Disease (PREVEND) Study . Am J Kidney Dis 2014 ; 63 : 415 – 421 Google Scholar Crossref Search ADS PubMed 58 Yuen JY , Kaysen GA. Acute phase proteins and peritoneal dialysate albumin are the main determinants of serum albumin in peritoneal dialysis patients . Am J Kidney Dis 1997 ; 30 : 923 – 927 Google Scholar Crossref Search ADS PubMed 59 Saito A. Definition of high-performance membranes – from the clinical point of view . Contrib Nephrol 2011 ; 173 : 1 – 10 Google Scholar Crossref Search ADS PubMed 60 Kaplan AA , Halley SE , Lapkin RA et al. Dialysate protein losses with bleach processed polysulphone dialyzers . Kidney Int 1995 ; 47 : 573 – 578 Google Scholar Crossref Search ADS PubMed 61 Tsuchida K , Minakuchi J. Albumin loss under the use of the high-performance membrane . Contrib Nephrol 2011 ; 173 : 76 – 83 Google Scholar Crossref Search ADS PubMed 62 Struijk DG , Krediet RT , Koomen GC et al. The effect of serum albumin at the start of continuous ambulatory peritoneal dialysis treatment on patient survival . Perit Dial Int 1994 ; 14 : 121 – 126 Google Scholar PubMed 63 Balafa O , Halbesma N , Struijk DG et al. Peritoneal albumin and protein losses do not predict outcome in peritoneal dialysis patients . Clin J Am Soc Nephrol 2011 ; 6 : 561 – 566 Google Scholar Crossref Search ADS PubMed 64 Jourde-Chiche N , Dou L , Cerini C et al. Vascular incompetence in dialysis patients–protein-bound uremic toxins and endothelial dysfunction . Semin Dial 2011 ; 24 : 327 – 337 Google Scholar Crossref Search ADS PubMed 65 Pletinck A , Glorieux G , Schepers E et al. Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall . J Am Soc Nephrol 2013 ; 24 : 1981 – 1994 Google Scholar Crossref Search ADS PubMed 66 Ito S , Yoshida M. Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients . Toxins (Basel) 2014 ; 6 : 665 – 678 Google Scholar Crossref Search ADS PubMed 67 Lesaffer G , De Smet R , Lameire N et al. Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane . Nephrol Dial Transplant 2000 ; 15 : 50 – 57 Google Scholar Crossref Search ADS PubMed 68 De Smet R , Dhondt A , Eloot S et al. Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-protein-bound and protein-bound uraemic solutes . Nephrol Dial Transplant 2007 ; 22 : 2006 – 2012 Google Scholar Crossref Search ADS PubMed 69 Himmelfarb J , McMonagle E. Albumin is the major plasma protein target of oxidant stress in uremia . Kidney Int 2001 ; 60 : 358 – 363 Google Scholar Crossref Search ADS PubMed 70 Suliman ME , Heimbürger O , Bárány P et al. Plasma pentosidine is associated with inflammation and malnutrition in end-stage renal disease patients starting on dialysis therapy . J Am Soc Nephrol 2003 ; 14 : 1614 – 1622 Google Scholar Crossref Search ADS PubMed 71 Berg AH , Drechsler C , Wenger J et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure . Sci Transl Med 2013 ; 5 : 175ra29 Google Scholar Crossref Search ADS PubMed 72 Lim PS , Jeng Y , Wu MY et al. Serum oxidized albumin and cardiovascular mortality in normoalbuminemic hemodialysis patients: a cohort study . PLoS One 2013 ; 8 : e70822 Google Scholar Crossref Search ADS PubMed 73 Terawaki H , Takada Y , Era S et al. The redox state of albumin and serious cardiovascular incidence in hemodialysis patients . Ther Apher Dial 2010 ; 14 : 465 – 471 Google Scholar Crossref Search ADS PubMed 74 Clavant SP , Comper WD. Urinary clearance of albumin is critically determined by its tertiary structure . J Lab Clin Med 2003 ; 142 : 372 – 384 Google Scholar Crossref Search ADS PubMed 75 Nagai K , Tsuchida K , Ishihara N et al. Implications of albumin leakage for survival in maintenance hemodialysis patients: a 7-year observational study . Ther Apher Dial 2017 ; 21 : 378 – 386 Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Hypoalbuminemia: a price worth paying for improved dialytic removal of middle-molecular-weight uremic toxins?
JF - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfy236
DA - 2019-06-01
UR - https://www.deepdyve.com/lp/oxford-university-press/hypoalbuminemia-a-price-worth-paying-for-improved-dialytic-removal-of-JpQoMENCQv
SP - 901
VL - 34
IS - 6
DP - DeepDyve
ER -