ß2-Microglobulin kinetics in nocturnal haemodialysis
Dominic S. C. Raj,
Michaelene Ouwendyk,
Robert Francoeur and
Andreas Pierratos1
Department of Medicine, Louisiana State University Medical Center, Shreveport, Louisiana, USA and
1 Nocturnal Hemodialysis Project, Wellesley Central Hospital and Humber River Regional Hospital, University of Toronto, Ontario, Canada
Correspondence and offprint requests to:
Andreas Pierratos MD, FRCPC, 2221 Keele St. #315 North York, Ontario, Canada M6M 3Z5.
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Abstract
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Background. ß2-Microglobulin (ß2m) is a major component of dialysis-related amyloidosis. The available therapeutic options do not permit normalization of the serum ß2m level. In a cross-over trial, we studied the kinetics of ß2m during two different dialytic techniques.
Methods. Ten stable, anuric end-stage renal disease patients were studied during two consecutive weeks of three conventional (CHD) and six nocturnal haemodialysis (NHD) sessions. CHD was performed for 4 h three times weekly using a polysulfone dialyser (F80, surface area of 1.8 m2) with a mean blood and dialysate flow rate of 401±91.6 and 514±10.9 ml/min, respectively. The NHD was done with a smaller dialyser (F40, surface area of 0.7 m2) and lower blood (281±17 ml/min) and dialysate flow rates (99±1.2 ml/min) for 8 h, six nights a week.
Results. Weekly removal of urea (51.6±24.6 vs 43.1±20.5 g) and creatinine (8501±5204 vs 6319±4134 mg) were comparable with the two modalities of dialysis but the mass of ß2m removed was significantly higher with NHD (127±48 vs 585±309 mg, P<0.001), with a percentage reduction in serum level of 20.5±5.8 vs 38.8±7.1% (P<0.0001) and a Kt/Vß2m of 0.21±0.09 vs 0.56±0.17 (P<0.0006). The mean post-dialysis ß2m (20.8±6.3 vs 14.0±3.8 mg/dl, P=0.02), Tacß2m (26.2±5.2 vs 19.8±3.8 mg/dl, P=0.02) and pre-dialysis ß2m (ß2mpre) at the end of 1 week of therapy (24.4±7.6 vs 19.0±3.4 mg/dl, P=0.02) were lower with NHD. Long-term follow-up data were available in 13 and seven patients at the end of 1 and 2 years, respectively. Serum ß2mpre levels progressively declined from 27.2±11.7 mg/dl at initiation of NHD to 13.7±4.4 mg/dl by 9 months, and they remained stable thereafter.
Conclusions. NHD provides a much higher clearance of ß2m than CHD, leading to a long-term decrease in the pre-dialysis concentration of ß2m.
Keywords: dialysis; home dialysis; ß2-microglobulin; nocturnal haemodialysis
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Introduction
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Dialysis-related amyloidosis (DRA) is a frequent complication in patients on maintenance haemodialysis [13]. Geyjo et al. demonstrated that the major component of amyloid protein in DRA is ß2-microglobulin (ß2m) [4]. Preliminary in vivo studies suggest that ß2m is not an inert molecule, but it exerts adverse biological activity especially at high concentrations [5,6], prompting the search for ways to normalize its concentration in renal failure. The removal of ß2m by diffusion, convection [7,8] and adsorption [9,10] by available highly permeable membranes ranges from 86 to 260 mg per dialysis, which is far less than the average daily synthesis of 180360 mg by a 60 kg patient [1113]. Odell et al., using a three compartment kinetic model for ß2m, concluded that intermittent dialysis can only remove about half the weekly load of ß2m [13]. Despite the bleak predictions that a negative balance is an impossible goal, it is reasonable to assume that a modest reduction in the level of ß2m may postpone the onset of DRA.
Nocturnal haemodialysis (NHD) is a slow, gentle, yet effective extracorporeal therapy that uses a highly permeable, biocompatible, small surface area membrane [14]. We report the comparative kinetics of ß2m and small molecular weight solutes in 10 patients who were switched from conventional haemodialysis (CHD) to NHD.
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Subjects and methods
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Patients
Ten end-stage renal disease (ESRD) patients on maintenance haemodialysis were studied. All the patients were virtually anuric and clinically stable. There were seven males and three females. The mean age and weight of the patients were 42.3±11.3 years and 58.8±51 kg, respectively. The aetiology of renal failure was chronic glomerulonephritis in three, reflux nephropathy in one, diabetes in two, chronic tubulo-interstitial nephropathy in one, polycystic kidney disease in one, hypertensive nephrosclerosis in one and unknown in one. Patients were treated with high-flux haemodialysis using F80 haemodialysers before entry into the study. The mean duration of haemodialysis prior to the study was 76.7±65.4 months (minimum 13 and maximum 186).
Clinical study protocol
The patients were monitored during three consecutive CHD sessions during 1 week and in a subsequent week during six sessions of slow NHD. Using the patient as his own control, the progressive change in ß2m profile during the two modalities of treatment were compared. Vascular access was achieved through an Uldall Cook internal jugular catheter (Cook critical care, Bloomington, IN) [15]. Bicarbonate-based dialysate was delivered by a volumetric control monitor (Series H, Fresenius Inc., Walnut Creek, CA). Ultrafiltration was monitored carefully and intra-and inter-dialytic complications were documented.
The CHD was performed three times weekly for 4 h with a polysulfone haemodialyser with a surface area of 1.8 m2 (Hemoflow F80, Fresenius AG). The blood flow rate was optimized on an individual patient basis, averaging at 401±91.6 ml/min. The dialysate flow rate was maintained at 514±10.9 ml/min. During NHD, the patients were dialysed for 8 h daily for six nights a week using a polysulfone dialyser with a surface area of 0.70 m2 (Hemoflow F40, Fresenius AG). The blood and dialysate flow rates were maintained at a lower rate of 281.75±17.17 and 99±1.2 ml/min, respectively. The mean recirculation rate was estimated to be in the range of 17.5 and 20.7%, with blood flow rates of 300 and 400 ml/min, respectively [15].
Methods
Pre- and post-dialysis blood samples were obtained from the arterial line for urea, creatinine and ß2m. Urea and creatinine were measured by multianalyser (Ektachem 500; Eastman Kodak clinical diagnostics, NY). We confirmed that the auto-analyser can measure urea and creatinine accurately in aqueous solutions even at very low concentrations. The ß2m concentration was determined by microparticle enzyme immunoassay (IMx system, Abbot Laboratories, Abbot Park, IL). The total spent dialysate was collected in a calibrated container from the initiation to the end of each dialysis session. The volume of the effluent dialysate was measured accurately. The contents of all the containers were stirred and mixed well, and a sample of 10 ml of the spent dialysate was withdrawn for biochemical analysis and frozen immediately at -10 to -15°C. The concentration of urea, creatinine and ß2m in the effluent was measured. The total amount of the substance removed was calculated from the concentration of the substances and the total volume of spent dialysate. The ß2mpost was corrected for changes in distribution volume (Cß2mpost) [16]. The Tacß2m was used as an index of time-averaged exposure of the system to ß2m, and the percentage reduction (PRß2m%) as a measure of clearance of the solute from the blood.
The kinetic study
During the mid-week dialysis session (2nd CHD and 3rd NHD), the concentration of urea and ß2m in the serum and spent dialysate was measured pre-dialysis, 15 min after initiation of the treatment, at the mid-point of dialysis (120 min in CHD, 240 min in NHD) and at the end of dialysis. From the mass of urea and ß2m removed (by total dialysate collection), the dialyser clearance (K), volume of distribution (V) and Kt/V for urea (Kt/VUrea) and ß2m (Kt/Vß2m) were calculated [1719].
where CD is the concentration of the solute in the spent dialysate, VD is the volume of spent dialysate, CMID is the concentration of the solute at the mid-point of dialysis and t the duration of dialysis.
where QUF=the ultrafiltration rate, Ci=initial concentration of solute, Cf=final concentration of solute after rebound equilibration and G=generation rate. ß2m generation was assumed to be 152 µg/kg/h [20].
The corresponding percentage reduction in the serum ß2m (PRß2m%) was also computed as follows:
To determine the post-dialysis rebound of ß2m, blood samples were obtained at 30, 60 and 120 min after termination of dialysis and the percentage of rebound was estimated at different time points [21]. The rebound rate (%) was calculated as follows:
where Cß2mpost is the serum ß2m concentration at the end of the dialysis session and Cß2mpostR is the ß2m concentration at different time points after dialysis.
The pre-dialysis serum ß2m level was measured while the patients were on CHD, prior to initiation of NHD and at monthly intervals thereafter in all patients. When this study was completed, 13 and seven patients had successfully completed 12 and 24 months of NHD in our centre. Dialysers were discarded after single use during the kinetic study, but the long-term data after the first year of follow-up is predominantly from re-used membranes.
Statistical methods
Statistical analysis was done with Minitab statistical software (Minitab Inc., Release 11, PA). The mean data from 30 observations in CHD and 60 observations in NHD were used for analysis. The data are given as mean±SD. The results of CHD are given before those of NHD throughout the text. Student's t-test was used to determine the significance of the difference between paired data, and the difference was taken as significant if P<0.05. Linear regression analysis was used to elucidate the relationship between the data groups.
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Results
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Solute removal
The total volume of dialysate collected during CHD and NHD was 126.4±10.0 and 52.4±1.3 l, respectively. The mean ultrafiltration during CHD and NHD was not significantly different (1.99±1.36 vs 1.1±0.77/l/session). While the mass of ß2m (Mß2m) removed during each session was significantly higher in NHD (42.4±16.2 vs 102.6±42.6 mg, P=0.0015), the mass of urea (MUr) (14.4±6.8 vs 9.4±2.8 g, P=0.06) and creatinine (MCr) (2106.0±1378.0 vs 1546.0±717.0 mg, P=0.27) removed per session was greater with CHD (Table 1
). Although the total cumulative weekly depuration of urea and creatinine was not different, the mass of ß2m removed by NHD per week was significantly higher (127.4±48.7 vs 585.2±309.2, P<0.001).
MUr and MCr declined progressively with successive NHD, but there was an impressive and sustained increase in Mß2m with NHD compared with CHD. Data analysis revealed a disparity in the relationship between the removal of different solutes with CHD and NHD. In CHD, the MUr was highly correlated with Mß2m (r2=0.72, P<0.001), while the correlation was only modest with MCr (r2=0.38, P<0.001). There was a poor correlation between Mß2m and other solutes in NHD (for MUr r2=0.28, P<0.001 and for MCr r2=0.2, P<0.01). Although Kt/VUrea per dialysis session was lower (0.99±0.30 vs 1.26±0.29, P<0.0001), the weekly Kt/VUrea was higher with NHD (6.17±0.85 vs 3.48±0.39, P<0.0001), resulting in a significantly lower TacUrea during NHD (18.4±6.3 vs 41.4±9.4, P<0.0001).
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ß2m profile
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Table 2
summarizes the serum ß2m profile observed during three CHD and six NHD sessions performed over 2 weeks. Uncorrected post-dialysis ß2m (ß2mpost) [16] was significantly higher than the corrected post-dialysis ß2m (Cß2mpost) (24.6±7.8 vs 20.8±6.3 mg/dl, P=0.05) in CHD, but the values were comparable in NHD (14.7±4.5 vs 14.0±3.8 mg/dl, P=0.5). Although the Cß2mpost was significantly lower in NHD (14.0±3.8 vs 20.8±6.3 mg/dl, P=0.001), the mean pre-dialysis ß2m (ß2mpre) during NHD and CHD was not significantly different (20.8±4.5 vs 26.1±8.2 mg/dl, P=0.1). However, despite a comparable ß2mpre at the initiation of CHD and NHD (24.4±9.1 vs 24.5±10.2, P=0.98), the ß2mpre at the end of 1 week of NHD was significantly lower with NHD (19.0±3.4 vs 24.4±7.6 mg/dl, P=0.02).
We observed that in spite of a marked reduction in ß2mpost, the ß2mpre level tends to bounce back to the pre-dialysis value prior to the next dialysis. The mean Tacß2m level, however, was significantly lower during NHD compared with CHD (19.8±3.8 vs 26.2±5.2 mg/dl, P=0.02).
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ß2m kinetics
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Figure 1
compares the serum and dialysate concentration of ß2m during the two dialysis procedures. The concentration of ß2m in the spent dialysate was higher and the mid-dialysis serum ß2m concentration lower during NHD. Enhanced clearance of ß2m manifested as a higher dialysate concentration and a marked decline of serum level of ß2m during NHD compared with CHD (Table 3
). The estimated volume of distribution of ß2m was 14.1±6.9 l which was ~19.6% of the body weight. The mean Kt/Vß2m was 0.21±0.09 for CHD, while it was 0.56±0.17 for NHD (P<0.0006), resulting in a PRß2m% of 20.5±5.8 and 38.8±7.1%, respectively (P<0.0001). As expected, there was a high degree of correlation between the Kt/Vß2m and PRß2m% (r2=0.81, P<0.001 for CHD). Figure 2
shows the PRß2m% and the rebound increase in serum ß2m post-dialysis. The rebound increase in serum ß2m at 30 min (4.03±5.8 vs 4.6±5.2%, P=NS), 60 min (7.8±2.9 vs 3.7±2.6%, P<0.01) and 120 min (6.9±3.7 vs 0.7±2.1%, P=0.06) was higher for CHD compared with NHD.

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Fig. 1. The serum and dialysate concentration of ß2m during NHD and CHD. Mid-dialysis represents 2 h in CHD and 4 h in NHD. The higher concentration of ß2m in the spent dialysate during NHD may be due to enhanced clearance or lower dialysate volume.
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Fig. 2. Although the percentage reduction of serum ß2m was significantly higher with NHD, the post-dialysis rebound was higher during CHD.
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Long-term follow-up
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Long-term follow-up data on the serum ß2m level were available in 13 and seven patients at the end of 12 and 24 months, respectively. Figure 3
demonstrates that there is slow but progressive decline in serum ß2m levels during NHD. The mean ß2mpre when the patients were on CHD was 27.2±8.1 mg/dl, which decreased to 13.7±4.4 mg/dl during 9 months of NHD (P<0.0001). With continued NHD, although the serum ß2m declined marginally further at the end of 24 months to 12.3±1.9 mg/dl, it was not statistically significant compared with the levels obtained at 12 months (P<0.22).
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Discussion
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The mass transfer of ß2m and its serum level are determined by the ultrafiltration coefficient [22], biocompatibility [23] and surface area of the membrane [24]. While the mass of urea removed correlated well with ß2m removal in CHD, the correlation was poor in NHD. We found that the depuration of ß2m is more efficient with NHD, as reflected by the intra-dialytic concentration profile of ß2m in serum and dialysate. The decline in ß2m clearance during high-flux dialysis [10,11] is probably a consequence of limitation of bulk mass transfer in the blood and dialysate compartments [25,26], secondary membrane formation [10], trans-cellular dysequilibrium [27,28], osmotic stress [29] and higher recirculation with higher blood flow rates. In contrast, the removal of ß2m in NHD is favoured by a longer duration of dialysis, allowing adequate equilibration. Jindal et al. reported that increasing the surface area of the polysulfone membrane from 1.3 to 1.9 m2 resulted in enhancement of the clearance by 72% [30]. Skroeder et al. investigated the effect of blood flow rate and duration of treatment on ß2m elimination during haemodialysis using cuprophane, haemophan and polyamide dialysers [31]. They reported that blood flow and the time factor did not influence ß2m removal when using cuprophane and haemophan membranes. Furthermore, removal of ß2m with polyamide membrane was significantly enhanced by the time factor, but not by blood flow rates [31]. However, the effect of time, the surface area of the membrane and the blood flow rate cannot be studied precisely with membranes with limited capacity for ß2m clearance. An increase in the blood flow rate can achieve higher clearance of ß2m only when the surface area of the membrane is also increased simultaneously. Despite using a smaller surface area membrane and low dialysate and blood flow rate, NHD achieved comparable weekly removal of small molecular weight solutes and significantly higher removal of ß2m. Thus, the higher ß2m removed during NHD may be explained largely by the longer duration of dialysis.
In most high-flux treatments, maximal removal of ß2m can be achieved only with high ß2mpre. Three hours of haemofiltration (HF), with the augmented convective component, allow a mean removal of 167±51 mg per session with a percentage reduction of 72±18% [32]. Haemodiafiltration (HDF) effectively combines diffusive and convective trans-membrane transport to remove ~148.7±17 mg of ß2m with a percentage reduction of 62.7% per 3 h session [33]. The mass of ß2m removed by NHD per session is only modest (103.0±42.6 mg) compared with these novel innovations. One possible explanation for this observation could be that our patients had a relatively lower ß2mpre (24.4±9.4 mg/dl) compared with the values reported in the literature (39.5±10.6 mg/dl) [34] at the start of the study. The lower ß2m levels observed could be because these patients were dialysed with high-flux polysulfone dialysers even prior to the study. Depuration of ß2m by NHD is predominantly through diffusion; the removal of ß2m could be further augmented by using a larger surface area membrane and by increasing the convective transport through ultrafiltration. Another mechanism of removal of ß2m not explored in this study is adsorption of ß2m by the membranes [35]. Kinetic studies using 131I-labelled ß2m revealed that the mean binding capacity in ß2m equivalent/m2 to be 16 mg/l for polysulfone, 54 mg/l for AN69, 58 mg/l for polyamide and 59 mg/l for polymethylmethacrylate [36]. Kandus et al. studied the adsorption of ß2m by AN69 at blood flow rates of 100 ml, 200 and 300 ml/min [37]. They concluded that increased contact time between the membrane and blood with lower blood flow rates may favour increased adsorption of ß2m on the dialysis membrane [37]. Although we do not have data about the quantity of ß2m adsorbed on the membrane, it is possible that adsorption also played a role in the removal of ß2m during NHD. The intra-dialytic kinetic study showed that the depuration of ß2m was higher during the first half of dialysis as evidenced by higher dialysate concentration and lower serum levels during this time (Figure 1
). This phenomenon may be explained by the observation that the higher sieving coefficient of polysulfone membrane for ß2m averages 1.0 in the first minute of blood contact with the membrane and decreases to a steady value of 0.30.4 after 1 h of dialysis [36]. The lower mid-dialysis serum ß2m concentration shown in Figure 1
should be interpreted in the light of the fact that mid-dialysis represents 2 h of dialysis in CHD and 4 h in NHD. Similarly, the higher concentration of ß2m in the effluent dialysate during NHD may be explained both by the enhanced depuration and the smaller dialysate volume used in NHD.
Kt/V urea is traditionally used as an estimate of the dose of dialysis [38]. Odell et al. suggested that Kt/V may be used to quantitate the dialytic removal of ß2m [13]. We calculated Kt/V for ß2m from the data obtained from the mid-week dialysis for a more precise and realistic estimation. Compared with CHD, NHD achieved a significantly higher Kt/Vß2m (0.56±0.17 vs 0.21±0.09, P<0.0006) and PRß2m% (38.8±7.1 vs 20.5±5.8%, P<0.0001 per session). The kinetics should be interpreted in the light of the fact that NHD is performed six times weekly. The estimated volume of distribution of ß2m as a fraction of body weight in our study was 19.6%, which is comparable with the 20% reported in the literature [39]. We submit that the concept of using Kt/V for quantification of ß2m clearance has not been validated so far and needs further exploration.
Kinetic studies have shown that a single compartment model is insufficient, a bi-compartmental model may explain the turnover of ß2m [40], but probably four compartments exist in patients on dialysis [41]. Karlsson et al. [42] and Vincent et al. [43] estimated the exchange rate constant through the capillary wall for ß2m to be 84.7 and 43.5 ml/h/kg, respectively. These exchange rates are much lower than the ß2m clearance of high efficiency dialysis, resulting in a higher rebound with high-flux dialysis. Hence it is not surprising that the longer and less intensive NHD achieves better clearance of ß2m. It is postulated that two types of rebound increase in ß2m occur post-dialysis; an early rebound due to mass transfer resistance between intra-and extravascular compartments and a late rebound due to ß2m generation in the intravascular compartment [20,44]. The peak rebound in serum ß2m was observed at 60 min post-dialysis and was significantly higher in CHD (7.8±2.9 vs 3.7±2.6, P<0.01). Despite a higher clearance, the rebound was attenuated in NHD because of ample time for equilibration between the compartments.
Odell et al. estimated that over a 10 year period an average individual produces and disposes of ~1 kg of ß2m [13]. In haemodialysis patients, the disposal routes are limited to partial or total catabolism and deposition of the complete or partial fragments as amyloid [39,44,45]. The threshold serum level beyond which the sequestration occurs is not yet known, but it is reasonable to speculate that a persistent reduction in Tacß2m may delay the onset of DRA. Canaud et al., by daily HF with AN69, were able to decrease the pre-dialysis ß2m concentration only to ~25 mg/dl despite a weekly removal rate of 985.0±20.0 mg of ß2m [46]. We observed that the mean ß2mpost and Tacß2m and ß2mpre at the end of 1 week of treatment were significantly lower in NHD compared with CHD. Kirkwood et al. postulated that it might take ~11 weeks for equilibration between the two compartments due to the very low trans-cellular mass transfer coefficient for molecules of medium molecular weight [28]. This is supported by the observation that a significant fall in the pre-dialysis value was obtained only after 2 months of continuous HDF [33,47], which is consistent with our results. We noted that the pre-dialysis ß2m levels progressively declined from 27.2±8.1 to 13.7±4.4 mg/dl by 9 months (P<0.0001). However, despite continuation of therapy, no further change in serum ß2m level was achieved at the end of 24 months, suggesting that the patients had reached a new state of equilibrium.
To conclude, NHD is an extracorporeal therapy which attempts to create a favourable and stable milieu by incorporating the steady-state of CAPD and the efficiency of HD to achieve adequate clearance of small and middle molecular weight solutes effectively. We submit that the normalization of the pre-dialysis ß2m level seems to be an impossible goal with NHD, as observed by others, but we trust that the decrease in the time-averaged concentration of ß2m may postpone, if not prevent, DRA.
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Acknowledgments
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This study was funded through a grant by the Ministry of Health of Ontario, Canada.
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Received for publication: 17.12.98
Accepted in revised form: 30. 8.99