Resistance to intercompartmental mass transfer limits β2-microglobulin removal by post-dilution hemodiafiltration
2006; Elsevier BV; Volume: 69; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5000048
ISSN1523-1755
AutoresRichard A. Ward, Tom Greene, Beate Hartmann, W. Samtleben,
Tópico(s)Erythropoietin and Anemia Treatment
ResumoAlthough clearance of β2-microglobulin is greater with hemodiafiltration than with high-flux hemodialysis, β2-microglobulin concentrations after long-term hemodiafiltration are only slightly less than those obtained with high-flux hemodialysis. Resistance to β2-microglobulin transfer between body compartments could explain this observation. β2-Microglobulin kinetics were determined in patients receiving on-line post-dilution hemodiafiltration for 4 h with 18 l of filtration. Plasma β2-microglobulin concentrations were measured during and for 2 h following hemodiafiltration and immediately before the next treatment. The filter clearance of β2-microglobulin was determined from arterial and venous concentrations. The β2-microglobulin generation rate was calculated from the change in the plasma concentration between treatments. The intercompartmental clearance was obtained by fitting the observed concentrations to a two-compartment, variable volume model. The plasma clearance of β2-microglobulin by the filter was 73±2 ml/min. Plasma β2-microglobulin concentrations decreased by 68±2% from pre- to post-treatment (27.1±2.2–8.5±0.7 mg/l), but rebounded by 32±3% over the next 90 min. The generation rate of β2-microglobulin was 0.136±0.008 mg/min. The model fit yielded an intercompartmental clearance of 82±7 ml/min and a volume of distribution of 10.2±0.6 l, corresponding to 14.3±0.7% of body weight. Hemodiafiltration provides a β2-microglobulin clearance of similar magnitude to the intercompartmental clearance within the body. As a result, intercompartmental mass transfer limits β2-microglobulin removal by hemodiafiltration. This finding suggests that alternative strategies, such as increased treatment times or frequency of treatment, are needed to further reduce plasma β2-microglobulin concentrations. Although clearance of β2-microglobulin is greater with hemodiafiltration than with high-flux hemodialysis, β2-microglobulin concentrations after long-term hemodiafiltration are only slightly less than those obtained with high-flux hemodialysis. Resistance to β2-microglobulin transfer between body compartments could explain this observation. β2-Microglobulin kinetics were determined in patients receiving on-line post-dilution hemodiafiltration for 4 h with 18 l of filtration. Plasma β2-microglobulin concentrations were measured during and for 2 h following hemodiafiltration and immediately before the next treatment. The filter clearance of β2-microglobulin was determined from arterial and venous concentrations. The β2-microglobulin generation rate was calculated from the change in the plasma concentration between treatments. The intercompartmental clearance was obtained by fitting the observed concentrations to a two-compartment, variable volume model. The plasma clearance of β2-microglobulin by the filter was 73±2 ml/min. Plasma β2-microglobulin concentrations decreased by 68±2% from pre- to post-treatment (27.1±2.2–8.5±0.7 mg/l), but rebounded by 32±3% over the next 90 min. The generation rate of β2-microglobulin was 0.136±0.008 mg/min. The model fit yielded an intercompartmental clearance of 82±7 ml/min and a volume of distribution of 10.2±0.6 l, corresponding to 14.3±0.7% of body weight. Hemodiafiltration provides a β2-microglobulin clearance of similar magnitude to the intercompartmental clearance within the body. As a result, intercompartmental mass transfer limits β2-microglobulin removal by hemodiafiltration. This finding suggests that alternative strategies, such as increased treatment times or frequency of treatment, are needed to further reduce plasma β2-microglobulin concentrations. β2-Microglobulin is an 11.8 kDa protein that comprises the light chain of the major histocompatibility complex present on the surface of all cells. After being shed from the cell surface, β2-microglobulin is eliminated from the circulation by glomerular filtration, followed by reabsorption and catabolism in the proximal tubule. As renal function decreases, β2-microglobulin is retained in the plasma and deposits as amyloid fibrils in many tissues. These amyloid deposits may cause carpal tunnel syndrome, arthropathy and bone cysts, and are a cause of morbidity in long-term hemodialysis patients.1.Miyata T. Jadoul M. Kurokawa K. van Ypersele de Strihou C. β2 microglobulin in renal disease.J Am Soc Nephrol. 1998; 9: 1723-1735PubMed Google Scholar In general, the clearance of β2-microglobulin by hemodialysis with low-flux membranes is negligible.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 3.Leypoldt J.K. Cheung A.K. Deeter R.B. Single compartment models for evaluating β2-microglobulin clearance during hemodialysis.ASAIO J. 1997; 43: 904-909Crossref PubMed Scopus (40) Google Scholar Clearance of β2-microglobulin by high-flux membranes is reported to be in the range of 17–22 ml/min;2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 3.Leypoldt J.K. Cheung A.K. Deeter R.B. Single compartment models for evaluating β2-microglobulin clearance during hemodialysis.ASAIO J. 1997; 43: 904-909Crossref PubMed Scopus (40) Google Scholar however, the rapid decrease in diffusive permeability with increasing molecular size limits β2-microglobulin clearance by diffusion no matter which membrane is used. To address the limited β2-microglobulin removal that can be obtained by diffusion, several investigators have turned to therapies based on convection, such as hemodiafiltration4.Kerr P.B. Argilés A. Flavier J.L. et al.Comparison of hemodialysis and hemodiafiltration: a long-term longitudinal study.Kidney Int. 1992; 41: 1035-1040Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 5.Locatelli F. Mastrangelo F. Redaelli B. et al.Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters.Kidney Int. 1996; 50: 1293-1302Abstract Full Text PDF PubMed Scopus (247) Google Scholar, 6.Wizemann V. Lotz C. Techert F. Uthoff S. On-line hemodiafiltration versus low-flux haemodialysis. A prospective randomized study.Nephrol Dial Transplant. 2000; 15: 43-48Crossref PubMed Scopus (161) Google Scholar, 7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar, 8.Lin C.L. Yang C.W. Chiang C.C. et al.Long-term on-line hemodiafiltration reduces predialysis beta-2-microglobulin levels in chronic hemodialysis patients.Blood Purif. 2001; 19: 301-307Crossref PubMed Scopus (64) Google Scholar or adsorption.9.Gejyo F. Teramura T. Ei I. et al.Long-term clinical evaluation of an adsorbent column (BM-01) of direct hemoperfusion type for β2-microobulin on the treatment of dialysis-related amyloidosis.Artif Organs. 1995; 19: 1222-1226Crossref PubMed Scopus (33) Google Scholar, 10.Ronco C. Brendolan A. Winchester J.F. et al.First clinical experience with an adjunctive hemoperfusion device designed specifically to remove β2-microglobulin in hemodialysis.Blood Purif. 2001; 19: 260-263Crossref PubMed Scopus (34) Google Scholar Hemodiafiltration provides dialyzer clearances of β2-microglobulin that are approximately twice those obtained with high-flux hemodialysis.7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar, 11.Lornoy W. Becaus I. Billiouw J.M. et al.Remarkable removal of beta-2-microglobulin by on-line hemodiafiltration.Am J Nephrol. 1998; 18: 105-108Crossref PubMed Scopus (66) Google Scholar In spite of this difference, predialysis β2-microglobulin concentrations remain at about 20 mg/l following long-term on-line hemodiafiltration,4.Kerr P.B. Argilés A. Flavier J.L. et al.Comparison of hemodialysis and hemodiafiltration: a long-term longitudinal study.Kidney Int. 1992; 41: 1035-1040Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 5.Locatelli F. Mastrangelo F. Redaelli B. et al.Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters.Kidney Int. 1996; 50: 1293-1302Abstract Full Text PDF PubMed Scopus (247) Google Scholar, 6.Wizemann V. Lotz C. Techert F. Uthoff S. On-line hemodiafiltration versus low-flux haemodialysis. A prospective randomized study.Nephrol Dial Transplant. 2000; 15: 43-48Crossref PubMed Scopus (161) Google Scholar, 7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar, 8.Lin C.L. Yang C.W. Chiang C.C. et al.Long-term on-line hemodiafiltration reduces predialysis beta-2-microglobulin levels in chronic hemodialysis patients.Blood Purif. 2001; 19: 301-307Crossref PubMed Scopus (64) Google Scholar a level that is not markedly lower than that achievable with high-flux hemodialysis when comparable blood flow rates and membrane surface areas are used.7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar It has long been recognized that disequilibrium develops between body compartments when dialytic removal exceeds the rate of transfer of solute from the extravascular compartment into the plasma.12.Popovich R.P. Hlavinka D.J. Bomar J.B. et al.The consequences of physiological resistances on metabolite removal from the patient–artificial kidney system.Trans Am Soc Artif Int Organs. 1975; 21: 108-115PubMed Google Scholar This disequilibrium leads to a rebound in plasma concentrations, post-dialysis, as the solute re-equilibrates between compartments once dialytic removal ceases. Previous studies have shown a rebound in plasma β2-microglobulin concentrations following modestly efficient high-flux hemodialysis.13.Maeda K. Shinzato T. Ota T. et al.Beta-2-microglobulin generation rate and clearance rate in maintenance hemodialysis patients.Nephron. 1990; 56: 118-125Crossref PubMed Scopus (26) Google Scholar, 14.Yasuhiro I. Eiichi N. Mineo O. et al.Removal of serum beta-2 microglobulin using high-performance membranes and analysis of changes in serum BMG levels after dialysis.Am J Nephrol. 1998; 18: 228-232Crossref PubMed Scopus (6) Google Scholar, 15.Leypoldt J.K. Cheung A.K. Deeter R.B. Rebound kinetics of β2-microglobulin after hemodialysis.Kidney Int. 1999; 56: 1571-1577Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Therefore, we hypothesized that the inability of long-term hemodiafiltration to markedly reduce plasma β2-microglobulin concentrations is a consequence of a significant mass transfer resistance between the vascular and extravascular compartments. To test this hypothesis, we determined the intercompartmental mass transfer coefficient for β2-microglobulin using plasma concentrations of β2-microglobulin obtained during and immediately following hemodiafiltration and a two-compartment kinetics model. The model was then used to assess the impact of changes in extracorporeal clearance and treatment frequency on β2-microglobulin removal. Ten patients (eight men and two women) were enrolled in the study. The patients ranged in age from 28 to 70 years (mean 56 years) and the etiology of their renal failure included glomerulonephritis (two patients), diabetes (two patients), hypertension (two patients), polycystic kidney disease (one patient) and was unknown for three patients. At the time of the study, nine of the patients were being treated with high-flux hemodialysis and one with hemodiafiltration. The duration of their dialysis therapy ranged from 24 to 74 months (mean 49 months). Details of the study treatments are given in Table 1. The treatment dose, as determined by the equilibrated Kt/V for urea,16.Daugirdas J.T. Schneditz D. Overestimation of hemodialysis dose depends on dialysis efficiency by regional blood flow but not by conventional two pool urea kinetic analysis.ASAIO J. 1995; 41: M719-M724Crossref PubMed Scopus (226) Google Scholar was 1.21±0.07. The plasma clearance of β2-microglobulin determined after 60 min of hemodiafiltration was 73±2 ml/min (equivalent to a whole blood clearance of 109±4 ml/min). β2-Microglobulin concentrations decreased by 68±2% during hemodiafiltration from 27.1±2.2 to 8.5±0.7 mg/l, then rebounded by 32±3%, corrected for generation, over the next 90 min by which time the rebound was complete (Figure 1). The post-hemodiafiltration concentration corrected for hemoconcentration by the method of Bergström and Wehle17.Bergström J. Wehle B. No change in corrected β2-microglobulin concentration after Cuprophane haemodialysis.Lancet. 1987; 1: 628-629Abstract PubMed Scopus (207) Google Scholar was 7.4±0.6 mg/l. The intercompartmental clearance and volume of distribution were estimated by fitting the model to the measured β2-microglobulin concentrations for each patient. Overall, the estimated intercompartmental clearance was 82±7 ml/min and the estimated volume of distribution was 10.2±0.6 l, corresponding to 14.3±0.7% of body weight. Estimated values of the two parameters for the individual patients are given in Table 2. Figure 2 presents the measured and modeled β2-microglobulin concentrations for a typical patient. The overall generation rate of β2-microglobulin, calculated using the estimated volume of distribution, was 0.136±0.008 mg/min.Table 1Details of study treatmentsTreatment time (TD, min)240Blood flow rate (QB, ml/min)280Hematocrit (t=60) (Hct)0.35±0.01Plasma flow rate (t=60) (QP, ml/min)aPlasma flow rate (QP) was determined from the blood flow rate (QB) and the fractional hematocrit (Hct) at the inlet to the hemodiafilter as QP=QB (1–Hct).182±3Weight, pretreatment (kg)73.4±3.2Weight, post-treatment (kg)71.2±3.3Net ultrafiltration rate (QUF, ml/min)9.1±1.4Total ultrafiltered volume (l)18Interdialytic interval (TID, min)2327±165Weight, post-interdialytic interval (kg)73.7±3.1Inter-dialytic fluid gain (α, ml/min)1.14±0.16Data are presented as mean±s.e.m. for n=10.a Plasma flow rate (QP) was determined from the blood flow rate (QB) and the fractional hematocrit (Hct) at the inlet to the hemodiafilter as QP=QB (1–Hct). Open table in a new tab Table 2Estimated kinetic model parameters for β2-microglobulinPatientIntercompartmental Clearance, KIC (ml/min)Distribution volume, VD=VP+VNP (l)Generation rate, G (mg/min) 110013.270.131 2867.520.131 3638.100.144 47512.310.091 5538.570.140 6579.250.125 710811.990.131 81029.910.165 9749.310.1821010711.370.115Data are presented as mean±s.e.m. for n=10. Open table in a new tab Figure 2Concentration profiles of β2-microglobulin in the perfused (solid line) and non-perfused (broken line) compartments obtained by fitting the kinetic model to measured plasma concentrations of β2-microglobulin (•) for a typical patient.View Large Image Figure ViewerDownload (PPT) Data are presented as mean±s.e.m. for n=10. Data are presented as mean±s.e.m. for n=10. Developing treatment strategies to remove β2-microglobulin, and thereby prevent or slow amyloid formation in patients with end-stage renal disease, requires an understanding of β2-microglobulin kinetics. Various kinetic models have been developed to describe β2-microglobulin kinetics during hemodialysis2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 19.Gotch F. Levin N. Zasuwa G. Tayeb J. Kinetics of beta-2-microglobulin in hemodialysis.Contrib Nephrol. 1989; 74: 132-138Crossref PubMed Google Scholar, 20.Lee C.J. Hsiong C.H. Chang Y.L. et al.Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.ASAIO J. 1994; 40: 62-66PubMed Google Scholar, 21.Lian J.D. Cheng C.H. Chang Y.L. et al.Clinical experience and model analysis on beta-2-microglobulin kinetics in high-flux hemodialysis.Artif Organs. 1993; 17: 758-763Crossref PubMed Scopus (17) Google Scholar and some of these models have been used to simulate β2-microglobulin removal with different treatment strategies.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar Two-compartment models have been the most widely used.18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 19.Gotch F. Levin N. Zasuwa G. Tayeb J. Kinetics of beta-2-microglobulin in hemodialysis.Contrib Nephrol. 1989; 74: 132-138Crossref PubMed Google Scholar, 20.Lee C.J. Hsiong C.H. Chang Y.L. et al.Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.ASAIO J. 1994; 40: 62-66PubMed Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar Single-compartment models are too simplistic based on the observation of a significant post-dialysis rebound in plasma β2-microglobulin concentration immediately following high-flux hemodialysis (Figure 1 and Yasuhiro et al.14.Yasuhiro I. Eiichi N. Mineo O. et al.Removal of serum beta-2 microglobulin using high-performance membranes and analysis of changes in serum BMG levels after dialysis.Am J Nephrol. 1998; 18: 228-232Crossref PubMed Scopus (6) Google Scholar), while models with three or more compartments suffer from problems of parameter estimation. The utility of two-compartment models depends on the estimation of several parameters that cannot be measured directly, including the compartment volumes, the inter-compartmental clearance and the generation rate of β2-microglobulin. Previous efforts to estimate these parameters have relied on infusing 125I-β2-microglobulin and fitting the plasma disappearance curve to the model.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 23.Vincent C. Chanard J. Caudwell V. et al.Kinetics of 125I-β2-microglobulin turnover in dialyzed patients.Kidney Int. 1992; 42: 1434-1443Abstract Full Text PDF PubMed Scopus (57) Google Scholar, 24.Floege J. Bartsch A. Schulze M. et al.Clearance and synthesis rates of β2-microglobulin in patients undergoing hemodialysis and in normal subjects.J Lab Clin Med. 1991; 118: 153-165PubMed Google Scholar This method has several drawbacks, including the need to prepare and infuse radiolabeled protein, the need to separate free 125I from 125I-β2-microglobulin in plasma samples and the assumption that kinetics following intravenous injection are the same as those occurring during and after an extracorporeal blood purification treatment. An alternative strategy involves fitting the model equations to plasma solute concentrations measured during and immediately following hemodialysis. The usefulness of this method has been limited by the relatively small reduction in plasma β2-microglobulin concentration that is effected by dialysis even with high-flux membranes.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 14.Yasuhiro I. Eiichi N. Mineo O. et al.Removal of serum beta-2 microglobulin using high-performance membranes and analysis of changes in serum BMG levels after dialysis.Am J Nephrol. 1998; 18: 228-232Crossref PubMed Scopus (6) Google Scholar Hemodiafiltration causes a much more pronounced decrease in plasma β2-microglobulin concentrations than does high-flux hemodialysis,7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar making the latter approach more amenable to estimating the model parameters. The model for β2-microglobulin kinetics used in this study differs from the two-pool models used by other investigators in several ways. In the present work, generation of β2-microglobulin was assumed to occur in both the perfused and the non-perfused compartments. Previous investigators have assumed that β2-microglobulin is generated in only one compartment.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 19.Gotch F. Levin N. Zasuwa G. Tayeb J. Kinetics of beta-2-microglobulin in hemodialysis.Contrib Nephrol. 1989; 74: 132-138Crossref PubMed Google Scholar, 20.Lee C.J. Hsiong C.H. Chang Y.L. et al.Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.ASAIO J. 1994; 40: 62-66PubMed Google Scholar, 21.Lian J.D. Cheng C.H. Chang Y.L. et al.Clinical experience and model analysis on beta-2-microglobulin kinetics in high-flux hemodialysis.Artif Organs. 1993; 17: 758-763Crossref PubMed Scopus (17) Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar However, β2-microglobulin is expressed on the surface of most nucleated cells making it more likely that free β2-microglobulin is generated in both compartments. Most prior investigations2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar have assumed that mass transfer of β2-microglobulin between the two compartments occurs by diffusion, only. We, along with Gotch and Keen,25.Gotch F.A. Keen M.L. Kinetic modeling in hemodialysis.in: Nissenson A.R. Fine R.N. Clinical Dialysis. 4th edn. McGraw-Hill, New York2005: 153-202Google Scholar have assumed that mass transfer also occurs by convection in conjunction with fluid movement between the two compartments. Finally, many prior studies of β2-microglobulin kinetics have assumed that the distribution volume for β2-microglobulin corresponds to extracellular fluid and they have also assumed that volume to be equal to one-third of the total body water.18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 20.Lee C.J. Hsiong C.H. Chang Y.L. et al.Statistical and parametric analysis of beta-2-microglobulin removal from uremic patients in high flux hemodialysis.ASAIO J. 1994; 40: 62-66PubMed Google Scholar, 21.Lian J.D. Cheng C.H. Chang Y.L. et al.Clinical experience and model analysis on beta-2-microglobulin kinetics in high-flux hemodialysis.Artif Organs. 1993; 17: 758-763Crossref PubMed Scopus (17) Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar We allowed the volume of distribution to vary and obtained an estimate based on the best fit of the model equations to the experimental data. The observed rebound in plasma β2-microglobulin concentration following hemodiafiltration was similar to that observed by Yasuhiro et al.14.Yasuhiro I. Eiichi N. Mineo O. et al.Removal of serum beta-2 microglobulin using high-performance membranes and analysis of changes in serum BMG levels after dialysis.Am J Nephrol. 1998; 18: 228-232Crossref PubMed Scopus (6) Google Scholar following high-flux hemodialysis, 31 versus 24%, respectively. The volume of distribution for β2-microglobulin derived from fitting the model to the experimental data was significantly less than that estimated from the anthropometric formulae of Watson et al.26.Watson P.E. Watson I.D. Batt R.D. Total body water volumes for adult males and females estimated from simple anthropometric measurements.Am J Clin Nutr. 1980; 33: 27-39PubMed Google Scholar (10.2±0.6 l or 14.3±0.7% of body weight compared to 12.8±0.6 l or 18.0±0.4% of body weight, P=0.0016). A similar discrepancy between the volume of distribution derived from experimental data and that calculated from anthropometric relationships has also been observed for urea.27.Kloppenburg W.D. Stegeman C.A. de Jong P.E. Huisman R.M. Anthropometry-based equations overestimate the urea distribution volume in hemodialysis patients.Kidney Int. 2001; 59: 1165-1174Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 28.Daugirdas J.T. Greene T. Depner T.A. et al.Anthropometrically estimated total body water volumes are larger than modeled urea volume in chronic hemodialysis patients: effects of age, race, and gender.Kidney Int. 2003; 64: 1108-1119Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The reasons for these differences are not known, but may include failure of the anthropometric method to account for the protein content of the plasma.27.Kloppenburg W.D. Stegeman C.A. de Jong P.E. Huisman R.M. Anthropometry-based equations overestimate the urea distribution volume in hemodialysis patients.Kidney Int. 2001; 59: 1165-1174Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 28.Daugirdas J.T. Greene T. Depner T.A. et al.Anthropometrically estimated total body water volumes are larger than modeled urea volume in chronic hemodialysis patients: effects of age, race, and gender.Kidney Int. 2003; 64: 1108-1119Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The calculated generation of β2-microglobulin (0.136±0.008 mg/day) is similar to that determined in normal subjects (0.162±0.016 mg/min29.Karlsson F.A. Groth T. Sege K. et al.Turnover in humans of β2-microglobulin: The constant chain of HLA antigens.Eur J Clin Invest. 1980; 10: 293-300Crossref PubMed Scopus (109) Google Scholar) and in dialysis patients using radiolabeled β2-microglobulin (0.158±0.015 mg/min,2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar 0.180±0.024 mg/min,23.Vincent C. Chanard J. Caudwell V. et al.Kinetics of 125I-β2-microglobulin turnover in dialyzed patients.Kidney Int. 1992; 42: 1434-1443Abstract Full Text PDF PubMed Scopus (57) Google Scholar 0.148±0.009 mg/min24.Floege J. Bartsch A. Schulze M. et al.Clearance and synthesis rates of β2-microglobulin in patients undergoing hemodialysis and in normal subjects.J Lab Clin Med. 1991; 118: 153-165PubMed Google Scholar), and in hemodialysis patients using methods similar to ours (0.132±0.006 mg/min,13.Maeda K. Shinzato T. Ota T. et al.Beta-2-microglobulin generation rate and clearance rate in maintenance hemodialysis patients.Nephron. 1990; 56: 118-125Crossref PubMed Scopus (26) Google Scholar 0.088±0.003 mg/min30.Xu X.Q. Gruner N. Al-Bashir A. et al.Determination of extra renal clearance and generation rate of β2-microglobulin in hemodialysis patients using a kinetic model.ASAIO J. 2001; 47: 623-627Crossref PubMed Scopus (12) Google Scholar). The estimated intercompartmental clearance for β2-microglobulin was 82±7 ml/min, similar to the 66±5 ml/min obtained by Floege et al.24.Floege J. Bartsch A. Schulze M. et al.Clearance and synthesis rates of β2-microglobulin in patients undergoing hemodialysis and in normal subjects.J Lab Clin Med. 1991; 118: 153-165PubMed Google Scholar following infusion of radiolabeled β2-microglobulin. Our model incorporates assumptions that may limit its applicability. Two assumptions concern fluid and solute transport between the perfused and non-perfused compartments. Changes in total fluid volume are assumed to be distributed between the perfused and non-perfused compartments in proportion to their volumes with no delay in fluid movement between the compartments. Delayed vascular refilling in response to ultrafiltration during a treatment would violate this assumption and reduce the accuracy of the model. A delay in vascular refilling would be marked by an increase in plasma protein concentration during the treatment followed by a prompt decrease in the immediate post-treatment period. We observed a small increase in serum albumin concentration during hemodiafiltration (3.7±0.2 to 3.9±0.2 g/dl) and no decrease in the immediate post-treatment period, indicating no delay in vascular refilling. Leypoldt et al. obtained a similar result in one study of high-flux hemodialysis,15.Leypoldt J.K. Cheung A.K. Deeter R.B. Rebound kinetics of β2-microglobulin after hemodialysis.Kidney Int. 1999; 56: 1571-1577Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar but not in another,31.Leypoldt J.K. Cheung A.K. Deeter R.B. et al.Kinetics of urea and β2-microglobulin during and after short hemodialysis treatments.Kidney Int. 2004; 66: 1669-1676Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar suggesting that delayed vascular refilling may occur under some circumstances. The nature of these circumstances is unclear, making it difficult to incorporate a lag term in the equations used to describe compartment volumes as a function of time. Unlike some previous models of β2-microglobulin kinetics,2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar, 22.Clark W.R. Leypoldt J.K. Henderson L.W. et al.Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.J Am Soc Nephrol. 1999; 10: 601-609PubMed Google Scholar our model assumes that solute transfer between the perfused and non-perfused compartments occurs by both diffusion and convection. The perfused and non-perfused compartments are generally assumed to represent plasma and the interstitium, in which case the transfer barrier is the capillary wall. We are unaware of any sieving coefficient data for low molecular weight proteins, such as β2-microglobulin, and the capillary wall. Harper et al.32.Harper S.J. Tomson C.R.V. Bates D.O. Human uremic plasma increases microvascular permeability to water and proteins in vivo.Kidney Int. 2002; 61: 1416-1422Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar have shown that a uremic environment significantly increases the protein permeability of the microvasculature. Given this observation, and in the absence of data, we have assumed that the sieving coefficient of the transfer barrier between the two compartments for β2-microglobulin is one. The impact of these two assumptions on the accuracy of the model is likely to depend on the magnitude of the ultrafiltration rate, with the impact being limited at the low net ultrafiltration rates used in our study. Another assumption in our model is that the extracorporeal clearance of β2-microglobulin is constant throughout the treatment. In hemodiafiltration, clearance of β2-microglobulin occurs through a combination of convection, diffusion and adsorption to the membrane. We combined these three mechanisms into a single total clearance, which was measured after 1 h of treatment. We have found that the clearance of the Polyflux S membrane used in this study remains essentially constant over the course of a single treatment given constant operating conditions (unpublished observations). However, this observation may not hold true for other membranes. Moreover, the practice of dialyzer reuse has been associated with both increases and decreases in β2-microglobulin clearance from treatment to treatment,33.Cheung A.K. Agodoa L.Y. Daugirdas J.T. et al.Effects of hemodialyzer reuse on clearances of urea and β2-microglobulin.J Am Soc Nephrol. 1999; 10: 117-127PubMed Google Scholar which would impact the accuracy of the model predictions shown in Figure 3 if hemodiafiltration was performed with reused hemodiafilters. Recognizing that convection provides higher clearances of large solutes, such as β2-microglobulin, many investigators have turned to hemofiltration and hemodiafiltration in the expectation that these therapies would decrease plasma β2-microglobulin concentrations and ameliorate the adverse effects of β2-microglobulin amyloid in long-term end-stage renal disease patients. The benefits obtained with these therapies, however, have been relatively modest, at least in terms of reducing pre-treatment plasma β2-microglobulin concentrations below those obtained with high-flux hemodialysis.4.Kerr P.B. Argilés A. Flavier J.L. et al.Comparison of hemodialysis and hemodiafiltration: a long-term longitudinal study.Kidney Int. 1992; 41: 1035-1040Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 5.Locatelli F. Mastrangelo F. Redaelli B. et al.Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters.Kidney Int. 1996; 50: 1293-1302Abstract Full Text PDF PubMed Scopus (247) Google Scholar, 7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar Even with 60 l of convection in the post-dilution mode, Wizemann et al.6.Wizemann V. Lotz C. Techert F. Uthoff S. On-line hemodiafiltration versus low-flux haemodialysis. A prospective randomized study.Nephrol Dial Transplant. 2000; 15: 43-48Crossref PubMed Scopus (161) Google Scholar could not reduce the pretreatment β2-microglobulin concentration below about 18 mg/l after 24 months. (It should be noted that the predialysis concentrations of β2-microglobulin reported in Figures 1 and 2 indicate nothing about the long-term effectiveness of hemodiafiltration because, with one exception, the patients participating in this study were normally treated with high-flux hemodialysis.) Our results show that the extracorporeal plasma clearance of β2-microglobulin obtained with hemodiafiltration (73±2 ml/min) approached the intercompartmental clearance (82±7 ml/min). Our kinetic analysis also shows that a substantial disequilibrium develops between the perfused and non-perfused compartments when the extracorporeal clearance and the intercompartmental clearance are similar in magnitude (Figure 2). The extent of this disequilibrium will increase as the extracorporeal clearance is increased relative to the intercompartmental clearance and the return on increasing the extracorporeal clearance will be limited as the greatest resistance to mass transfer limits solute removal. This situation is shown in Figure 3a, which depicts the plasma β2-microglobulin concentration profile predicted using our model over a 1-week period for thrice-weekly high-flux hemodialysis (extracorporeal clearance 25 ml/min), hemodiafiltration (extracorporeal clearance 75 ml/min) and hemoadsorption (extracorporeal clearance 150 ml/min). These calculated profiles show a diminishing return in terms of reducing the plasma β2-microglobulin concentration as clearance increases and suggest that the benefits to be derived from hemoadsorption may be limited. On the other hand, application of our model suggests that increasing the frequency of treatment may have a marked effect on the plasma concentration of β2-microglobulin (Figure 3b). The model predicts mid-week serum β2-microglobulin concentrations of 23 and 17 mg/l for 2 h of hemodiafiltration and 8 h of high-flux hemodialysis, 6 days per week, respectively, compared to 25 mg/l for 4 h of hemodiafiltration, 3 days per week. These model predictions are in good agreement with clinical observations reported in the literature. We have previously reported a mid-week serum β2-microglobulin concentration of 23 mg/l in 24 patients treated with thrice-weekly on-line hemodiafiltration for 12 months.7.Ward R.A. Schmidt B. Hullin J. et al.A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study.J Am Soc Nephrol. 2000; 11: 2344-2350PubMed Google Scholar Maduell et al.34.Maduell F. Navarro V. Torregrosa E. et al.Change from three times a week on-line hemodiafiltration to short daily on-line hemodiafiltration.Kidney Int. 2003; 64: 305-313Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar reported a mid-week serum β2-microglobulin concentration of 23 mg/l in eight patients treated for 6 months with 2–2.5 h of on-line hemodiafiltration 6 days per week, whereas Canaud et al.35.Canaud B. Assounga A. Kerr P. et al.Failure of a daily haemofiltration programme using a highly permeable membrane to return β2-microglobulin concentrations to normal in haemodialysis patients.Nephrol Dial Transplant. 1992; 7: 924-930PubMed Google Scholar reported a concentration of around 25 mg/l in seven patients treated daily with 3 h of hemofiltration. It should be noted that the β2-microglobulin clearance was lower in the latter study than is assumed in Figure 3. Finally, Raj et al.36.Raj D.S.C. Ouwendyk M. Francoeur R. Pierratos A. β2-microglobulin kinetics in nocturnal haemodialysis.Nephrol Dial Transplant. 2000; 15: 58-64Crossref PubMed Scopus (139) Google Scholar reported a mid-week serum β2-microglobulin concentration of 14 mg/l in 13 patients treated for 9 months with 8 h of high-flux hemodialysis six nights per week. In summary, the results of this kinetic study suggest that the development of on-line convective therapies, such as hemodiafiltration, has led to the situation where β2-microglobulin removal is controlled as much by intercompartmental transfer within the body as by the extracorporeal clearance of β2-microglobulin. This finding, as illustrated by the simulations in Figure 3, suggests that returning serum β2-microglobulin concentrations to a more normal level will be best achieved by concentrating on the time and frequency of therapy rather than through strategies designed to increase the extracorporeal clearance. Plasma β2-microglobulin concentrations were determined during a single mid-week hemodiafiltration treatment and the following intertreatment period. Hemodiafiltration was performed in the post-dilution mode using on-line preparation of substitution solution (AK 100 ULTRA, Gambro, Hechingen, Germany). All treatments were performed with dialyzers containing high-flux membranes based on polyarylethersulfone (Polyflux 17S, Gambro). The treatment time was 240 min, with blood and total dialysate flow rates fixed at 280 and 500 ml/min, respectively. The total filtration volume was set at 18 l. Net fluid removal was set according to the patients' clinical needs. Other aspects of the treatment were according to the patient's routine prescription. Patients were required to have a hematocrit of at least 30% and a blood access capable of delivering a flow rate of 280 ml/min to be eligible for participation in the study. Exclusion criteria included a residual urine output of more than 200 ml/day or an infection within 30 days of the study. Blood samples were collected following insertion of the first access needle and from the arterial blood line after 60, 120 and 240 min of hemodiafiltration. A venous blood sample was also collected at 60 min to allow calculation of the plasma water clearance of β2-microglobulin by the dialyzer. Immediately after collection of the 240 min blood sample, the blood flow rate was reduced to 80 ml/min and a blood sample was collected 20 s later. Subsequent blood samples were obtained at 5, 10, 30, 60, 90, 120, and 240 min after the end of the treatment, and immediately before the next treatment. All samples were placed in tubes containing ethylenediaminetetraacetic acid and the plasma was separated by centrifugation. Samples were stored at -70°C until analysis for β2-microglobulin by nephelometry. The Ethics Committee of the University of Munich reviewed the study protocol and each patient gave informed consent before participating in the study. β2-Microglobulin kinetics were determined using a modification of a two-pool model previously described by Kanamori and Sakai18.Kanamori T. Sakai K. An estimate of β2-microglobulin deposition rate in uremic patients on hemodialysis using a mathematical kinetic model.Kidney Int. 1995; 47: 1453-1457Abstract Full Text PDF PubMed Scopus (23) Google Scholar (Figure 4). The model assumes that β2-microglobulin is distributed in two compartments: a perfused compartment, to which the dialyzer has direct access, and a non-perfused compartment. Transfer of β2-microglobulin between the two compartments is assumed to occur by diffusion, with an intercompartmental clearance, KIC, and convection, with an intercompartmental sieving coefficient of one. Generation (G) is assumed to occur in both compartments in proportion to their volumes. Non-renal clearance (KNR) of β2-microglobulin is assumed to occur in the perfused compartment. The change in mass of β2-microglobulin in the two compartments can be described as a function of time (t) by the following two equations. Perfused compartmentd(VPCP)dt=ΦPG+KIC(CNP−CP)−ΘKDCP−KNRCP+ΘΦNPQUFCNP−(1−Θ)ΦNPαCP(1) Non-perfused compartmentd(VNPCNP)dt=ΦNPG+KIC(CP−CNP)−ΘΦNPQUFCNP+(1−Θ)ΦNPαCP(2) where VP and VNP are the volumes of the perfused and non-perfused compartments, respectively, CP and CNP are the concentrations in the perfused and non-perfused compartments, respectively, KD is the dialyzer clearance, QUF is the ultrafiltration rate, α is the rate of fluid intake in the interdialytic period, ΦP and ΦNP are the fractions of the total distribution volume in the perfused and non-perfused compartments, respectively, and, Θ is an indicator variable such that Θ=1 during dialysis and Θ=0 in the interdialytic period. A similar pair of equations describes the change in volume of the two compartments during dialysis as a function of time. Intradialytic fluid removal and interdialytic fluid intake are assumed to occur in both the perfused and non-perfused compartments in proportion to their relative volumes. Perfused compartmentdVPdt=−ΘΦPQUF+(1−Θ)ΦPα(3) Nonperfused compartmentdVNPdt=−ΘΦNPQUF+(1−Θ)ΦNPα(4) The generation rate of β2-microglobulin (G) was calculated from the distribution volume (VD=VP+VNP) and the change in plasma concentration between the end of the post-treatment rebound and the beginning of the next treatment. For this purpose, the post-treatment rebound was assumed to be complete 240 min after the end of the treatment.G=(KNR+α)(CNEXT−C480(VD480/VDNEXT)(KNR+α)/α)1−(VD480/VDNEXT)(KNR+α)/αwhere the subscripts 480 and NEXT refer to 240 min after the end of the treatment and the beginning of the next treatment, respectively. The plasma clearance of β2-microglobulin by the dialyzer, KD, was calculated using the following standard equation for clearance:KD=QB(1−Hct)(CA−CV)CA+QUFCVCAwhere QB is the blood flow rate, Hct is the fractional hematocrit, and CA and CV are the β2-microglobulin concentrations at the inlet and the outlet of the dialyzer, respectively. The non-renal clearance of β2-microglobulin, KNR, was assumed to be 3 ml/min.2.Odell R.A. Slowiaczek P. Moran J.E. Schindhelm K. Beta2-microglobulin kinetics in end-stage renal failure.Kidney Int. 1991; 39: 909-919Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 37.Floege J. Wilks M. Shaldon S. et al.β2-Microglobulin kinetics during haemofiltration.Nephrol Dial Transplant. 1988; 3: 784-789PubMed Google Scholar Equations (1), (2), (3) and (4) were solved numerically using a fourth order Runge–Kutta method.38.Forsythe G.E. Malcolm M.A. Moler C.B. Computer Methods for Mathematical Computations. Prentice-Hall, Englewood Cliffs, NJ1977Google Scholar The ratio of the perfused volume to the non-perfused volume was assumed to be 1:3, such that ΦP=0.25 and ΦNP=0.75. The intercompartmental clearance, KIC, and the volume of distribution, VD=VP+VNP, were estimated by determining the best fit of the equations to the plasma concentration versus time data using a least-squares method. The rebound in plasma β2-microglobulin concentration following the end of hemodiafiltration was calculated asPercent Rebound=100×(CT−C240)C240where C240 and CT are the solute concentrations at the end of dialysis and T minutes after the end of dialysis, respectively. Data are presented as mean±s.e.m. for n observations. We thank Christina Dengler for her help in sample collection and analysis and the nursing staff of the KfH Kidney Center Neuried.
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