Superior dialytic clearance of β2-microglobulin and p-cresol by high-flux hemodialysis as compared to peritoneal dialysis
2006; Elsevier BV; Volume: 70; Issue: 4 Linguagem: Inglês
10.1038/sj.ki.5001640
ISSN1523-1755
AutoresPieter Evenepoel, Bert Bammens, Kristin Verbeke, Yves Vanrenterghem,
Tópico(s)Pharmacological Effects and Toxicity Studies
ResumoBoth residual renal and dialytic clearance confer to the total solute clearance in dialysis patients. Dialytic clearances of the middle molecule beta-microglobulin (β2M) and the protein-bound solute p-cresol (pcr) are generally believed to be higher with peritoneal dialysis (PD) as compared to hemodialysis (HD). Supportive data, however, are lacking. We performed a single-center cross-sectional observational study including 70 unselected patients treated with either high-flux HD (n=20) or PD (n=50). Mid-day serum levels (PD) and time-averaged concentrations (HD) of the water-soluble solutes urea nitrogen, creatinine and phosphate, the middle molecule β2M, and the protein-bound solute pcr were determined. Dialytic solute clearances (l/week/1.73 m2) were calculated from total dialysate collection during the mid-week session in HD and 24 h dialysate collection in PD. Renal clearances were calculated for each of the respective solutes from a timed urine collection. Total clearances were obtained by summation. HD delivered significantly higher clearances of all retention solutes studied. This superiority was especially pronounced for pcr (30.9±62.7 vs 4.4±2.3, HD vs PD, P<0.0001) and β2M (28.6±6.6 vs 5.8±3.1, HD vs PD, P<0.0001). Renal clearances, conversely, were significantly higher in patients on PD. Serum levels of all solutes but pcr were significantly lower in HD than in PD. Both a higher residual renal function and a lower generation rate contribute to the lower pcr levels in PD. In conclusion, superior dialytic clearance of both water-soluble solutes, β2M, and pcr is achieved by high-flux HD as compared to PD. Both residual renal and dialytic clearance confer to the total solute clearance in dialysis patients. Dialytic clearances of the middle molecule beta-microglobulin (β2M) and the protein-bound solute p-cresol (pcr) are generally believed to be higher with peritoneal dialysis (PD) as compared to hemodialysis (HD). Supportive data, however, are lacking. We performed a single-center cross-sectional observational study including 70 unselected patients treated with either high-flux HD (n=20) or PD (n=50). Mid-day serum levels (PD) and time-averaged concentrations (HD) of the water-soluble solutes urea nitrogen, creatinine and phosphate, the middle molecule β2M, and the protein-bound solute pcr were determined. Dialytic solute clearances (l/week/1.73 m2) were calculated from total dialysate collection during the mid-week session in HD and 24 h dialysate collection in PD. Renal clearances were calculated for each of the respective solutes from a timed urine collection. Total clearances were obtained by summation. HD delivered significantly higher clearances of all retention solutes studied. This superiority was especially pronounced for pcr (30.9±62.7 vs 4.4±2.3, HD vs PD, P<0.0001) and β2M (28.6±6.6 vs 5.8±3.1, HD vs PD, P<0.0001). Renal clearances, conversely, were significantly higher in patients on PD. Serum levels of all solutes but pcr were significantly lower in HD than in PD. Both a higher residual renal function and a lower generation rate contribute to the lower pcr levels in PD. In conclusion, superior dialytic clearance of both water-soluble solutes, β2M, and pcr is achieved by high-flux HD as compared to PD. Although renal transplantation offers the best hope to patients with end-stage renal disease, only a small fraction of the incident end-stage renal disease population will get that opportunity, leaving the majority to receive either hemodialysis (HD) or peritoneal dialysis (PD). Despite tremendous advances in dialysis technology and considerable improvements in the delivery of health care, the survival of dialysis patients who reach end-stage renal disease has not improved substantially over the last decade.1.US Renal Data System USRDS 2002 Annual Data Report.Atlas of End Stage Renal Disease in The United States. National Insititue of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2002Google Scholar For these patients, defining the optimal dose of dialysis (dialysis adequacy) and optimal modality strategy remain critical components of patient management to ensure optimal survival. Traditionally, dialysis adequacy has been quantified referring to the kinetics of urea nitrogen (UN), taken as a paradigm of all uremic toxins, and applying the principles of pharmacokinetics using either single- or double-pool variable volume models (Kt/Vurea). Recent landmark studies such as the Hemodialysis (HEMO) and adequacy of dialysis Mexico (ADMEX) trial, however, failed to demonstrate a benefit on patient survival by increasing Kt/V urea well above the minimum requirements of current American and European guidelines. Moreover, the ADEMEX trial and other studies emphasized the importance of residual renal function (RRF) as a predictor of survival in dialysis patients.2.Eknoyan G. Beck G.J. Cheung A.K. et al.Hemodialysis (HEMO) Study Group… Effect of dialysis dose and membrane flux in maintenance hemodialysis.N Engl J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1085) Google Scholar, 3.Paniagua R. Amato D. Vonesh E. et al.Mexican Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial.J Am Soc Nephrol. 2002; 13: 1307-1320Crossref PubMed Scopus (1581) Google Scholar, 4.Bargman J.M. Thorpe K.E. Churchill D.N. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study.J Am Soc Nephrol. 2001; 12: 2518-2562Google Scholar, 5.Termorshuizen F. Dekker F.W. Van Manen J.G. et al.NECOSAD Study Group. Relative contribution of residual renal function and different measures of adequacy to survival in hemodialysis patients: an analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2.J Am Soc Nephrol. 2004; 15: 1061-1070Crossref PubMed Scopus (280) Google Scholar Several hypotheses have been formulated to explain this finding. In the presence of RRF, the maintenance of an adequate fluid balance is facilitated, the level of systemic inflammation is lower, and renal endocrine functions are preserved.6.Ates K. Nergizoglu G. Keven K. et al.Effect of fluid and sodium removal on mortality in peritoneal dialysis patients.Kidney Int. 2001; 60: 767-776Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar, 7.Burkart J.M. ADEMEX study and PD adequacy.Blood Purif. 2003; 21: 37-41Crossref PubMed Scopus (12) Google Scholar, 8.Pecoits-Filho R. Goncalves S. Barberato S.H. et al.Impact of residual renal function on volume status in chronic renal failure.Blood Purif. 2004; 22: 285-292Crossref PubMed Scopus (40) Google Scholar The beneficial impact of RRF may also be related to the preservation of specific renal elimination mechanisms such as tubular metabolism or secretion, which – as has been demonstrated recently – are crucial for the removal of the middle molecule beta-microglobulin (β2M) and the protein-bound retention solutep-cresol (pcr).9.Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Removal of middle molecules and protein-bound solutes by peritoneal dialysis and relation with uremic symptoms.Kidney Int. 2003; 64: 2238-2243Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar,10.Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Time profiles of peritoneal and renal clearances of different uremic solutes in incident peritoneal dialysis patients.Am J Kidney Dis. 2005; 46: 512-519Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Altogether, these findings stimulated scientist and clinicians to (re)consider middle molecules and protein-bound retention solutes as useful (additional) markers of dialysis adequacy. It has been reported that middle molecules, suppress the appetite, inhibit granulocyte function, and influence survival independently of small molecular solute clearance.11.Cohen G. Haag-Weber M. Hörl W.H. Immune dysfunction in uremia.Kidney Int Suppl. 1997; 62: S79-S82PubMed Google Scholar,12.Leypoldt J.K. Cheung A.K. Caitlin E.C. et al.Effects of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival.Am J Kidney Dis. 1999; 33: 349-355Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar β2M is a major representative of the middle molecules and is implicated in the formation of osteoarticular amyloid deposits.13.Floege J. Ketteler M. Beta2-microglobulin-derived amyloidosis: an update.Kidney Int Suppl. 2001; 78: S164-S171Crossref PubMed Google Scholar pcr is considered the prototype of the protein-bound retention solutes. It has been demonstrated in vitro to inhibit several biochemical, biological, and physiological functions.14.Vanholder R. De Smet R. Lesaffer G. p-Cresol: a toxin revealing many neglected but relevant aspects of uraemic toxicity.Nephrol Dial Transplant. 1999; 14: 2813-2815Crossref PubMed Scopus (87) Google Scholar Serum concentrations of pcr have recently emerged as a predictor of morbidity and mortality in HD patients.15.De Smet R. Van Kaer J. Van Vlem B. et al.Toxicity of free p-cresol: a prospective and cross-sectional analysis.Clin Chem. 2003; 49: 470-478Crossref PubMed Scopus (109) Google Scholar,16.Bammens B. Evenepoel P. Keuleers H. et al.Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients.Kidney Int. 2006; 69: 1081-1087Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar It is well known that PD and HD remove about the same amount of UN17.Chen T.W. Huang T.P. Liu M.C. Wang M.L. The removal index for evaluation of dialysis.Perit Dial Int. 1996; 16: 128-134PubMed Google Scholar and phosphate.18.Ketteler M. Gross M.L. Ritz E. Calcification and cardiovascular problems in renal failure.Kidney Int Suppl. 2005; 94: S120-S127Abstract Full Text Full Text PDF PubMed Google Scholar Information on the performance of PD as compared to high-flux HD in eliminating pcr and β2M, conversely, is limited or non-existing. The aim of this cross-sectional observational study was (i) to compare the clearance of pcr and β2M in an average (unselected) population of PD and high-flux HD patients and (ii) to investigate the relative contribution of dialytic and renal clearances to the overall clearances. Patient characteristics are depicted in Table 1. The patients treated with PD were significantly younger and had a better RRF as compared to the patients on HD. Gender, renal diagnosis, dialysis vintage, and comorbidity were similar in the two groups. The total dwell volume and number of exchanges was significantly higher in patients on automated peritoneal dialysis (APD) as compared to continuous ambulatory peritoneal dialysis (CAPD). The total dwell time, conversely, was significantly longer in patients on CAPD.Table 1Patient characteristicsHDAPDCAPDOverall ANOVAn203416—Age (years)68.8±10.9x,yParameters with same suffix differ significantly.50.1±18.7xParameters with same suffix differ significantly.54.2±13.8yParameters with same suffix differ significantly.0.0007Male/female15/520/149/70.4Renal diagnosis Cystic4420.8 Diabetic251— Glomerular9106— Tubulointerstitial363— Unknown063— Vascular231—Dialysis duration (months)19.3±31.513.0±10.812.0±8.00.624-h urine output (ml)240±379x,yParameters with same suffix differ significantly.749±645xParameters with same suffix differ significantly.751±589yParameters with same suffix differ significantly.0.0003GFR (ml/min/1.73 m2)1.39±2.34x,yParameters with same suffix differ significantly.3.22±2.61xParameters with same suffix differ significantly.4.16±2.77yParameters with same suffix differ significantly.0.001Anuria (yes/no)13/7x,yParameters with same suffix differ significantly.7/27xParameters with same suffix differ significantly.2/14yParameters with same suffix differ significantly.0.0006Treatment volume (ml)—11 735±28899000±15600.00124-h peritoneal drainage (ml)—13 223±348210 465±21000.00924-h ultrafiltration volume (ml)—1066±10851358±14810.4Icodextrin usage (yes/no)—15/198/80.7PET H/HA/LA/L/missing—0/7/14/5/81/1/3/8/30.03Preceding peritonitis (n)—0.5±1.00.6±1.60.6Exchanges (n)—5.5±1.14.2±0.50.0001Dwell time (h)—18.5±7.324.0±0.00.007Body weight (kg)59.9±7.967.0±14.067.9±10.40.08BSA (m2)1.66±0.151.76±0.231.76±0.180.2Comorbidity (low/medium/high grade)4/12/413/17/48/8/00.21Diabetes (yes/no)2/187/271/150.3ANOVA, analysis of variance; APD, automated peritoneal dialysis; BSA, body surface area; CAPD, continuous ambulatory peritoneal dialysis; GFR, glomerular filtration rate; PET, pertioneal equilibration test.x,y Parameters with same suffix differ significantly. Open table in a new tab ANOVA, analysis of variance; APD, automated peritoneal dialysis; BSA, body surface area; CAPD, continuous ambulatory peritoneal dialysis; GFR, glomerular filtration rate; PET, pertioneal equilibration test. Dialytic, renal, and total clearances in patients treated with HD and PD are summarized in Table 2. HD delivered significantly higher clearances of all uremic retention solutes studied. This superiority was especially pronounced for pcr and β2M and persisted after normalization to dialytic UN clearances (Figure 1). Renal clearances, conversely, were higher in patients on PD. As is evident from the total clearances, the higher renal clearance in PD failed to compensate for the inferior dialytic clearance for all solutes but creatinine (Figure 2). Renal clearance was the major route of elimination of β2M and pcr in patients on PD only. Dialytic and renal clearances of pcr and β2M were higher in patients on CAPD as compared to APD. Significance, however, was not reached.Table 2Dialytic, renal, and Clts in HD (n=20), APD (n=34), and CAPD (n=16) patientsHDAPDCAPDOverall ANOVAUN Clt (l/week/1.73 m2)140.7±31.9x,yParameters with same suffix differ significantly.83.1±12.4xParameters with same suffix differ significantly.102.0±32.8yParameters with same suffix differ significantly.<0.0001 Dialytic clearance (l/week/1.73 m2)130.8±26.9x,yParameters with same suffix differ significantly.61.0±17.1xParameters with same suffix differ significantly.72.4±30.9yParameters with same suffix differ significantly.<0.0001 Dialytic clearance, % of Clt94. 0±9.4x,yParameters with same suffix differ significantly.74.2±19.2xParameters with same suffix differ significantly.71.1±16.8yParameters with same suffix differ significantly.<0.0001 Clr (l/week/1.73 m2)9.8±16.0x,yParameters with same suffix differ significantly.22.1±18.5xParameters with same suffix differ significantly.29.5±20.0yParameters with same suffix differ significantly.<0.0001 Clr, % of Clt6.0±9.4x,yParameters with same suffix differ significantly.25.8±19.2xParameters with same suffix differ significantly.28.9±16.8yParameters with same suffix differ significantly.<0.0001Cr Clt (l/week/1.73 m2)101.8±35.184.1±26.1104.0±40.70.05 Dialytic clearance (l/week/1.73 m2)83.6±18.5x,yParameters with same suffix differ significantly.41.8±16.0xParameters with same suffix differ significantly.49.6±19.2yParameters with same suffix differ significantly.<0.0001 Dialytic clearance, % of Clt86.9±18.2x,yParameters with same suffix differ significantly.55.0±26.1xParameters with same suffix differ significantly.51.8±21.4yParameters with same suffix differ significantly.<0.0001 Clr (l/week/1.73 m2)18.2±31.2x,yParameters with same suffix differ significantly.42.2±32.9xParameters with same suffix differ significantly.54.5±38.2yParameters with same suffix differ significantly.0.001 Clr, % of Clt13.1±18.2x,yParameters with same suffix differ significantly.45.0±26.1xParameters with same suffix differ significantly.48.2±21.4yParameters with same suffix differ significantly.0.0001P Clt (l/week/1.73 m2)79.8±19.4xParameters with same suffix differ significantly.54.8±16.1xParameters with same suffix differ significantly.65.7±20.10.0001 Dialytic clearance (l/week/1.73 m2)68.6±15.2x,yParameters with same suffix differ significantly.32.7±14.8xParameters with same suffix differ significantly.40.2±13.0yParameters with same suffix differ significantly.<0.0001 Dialytic clearance, % of Clt88.9±14.8x,yParameters with same suffix differ significantly.62.7±26.7xParameters with same suffix differ significantly.63.0±18.3yParameters with same suffix differ significantly.0.0003 Clr (l/week/1.73 m2)10.5±14.5yParameters with same suffix differ significantly.22.1±19.625.5±18.3yParameters with same suffix differ significantly.0.01 Clr, % of Clt11.1±14.8x,yParameters with same suffix differ significantly.37.3±26.7xParameters with same suffix differ significantly.37.0±18.3yParameters with same suffix differ significantly.0.0003Pcr Clt (l/week/1.73 m2)34.2±62.2xParameters with same suffix differ significantly.11.4±8.6xParameters with same suffix differ significantly.20.0±13.60.001 Dialytic clearance (l/week/1.73 m2)30.9±62.7x,yParameters with same suffix differ significantly.3.7±1.7xParameters with same suffix differ significantly.5.8±2.6yParameters with same suffix differ significantly.<0.0001 Dialytic clearance, % of Clt88.5±19.5x,yParameters with same suffix differ significantly.45.5±28.9xParameters with same suffix differ significantly.40.9±26.4yParameters with same suffix differ significantly.<0.0001 Clr (l/week/1.73 m2)3.3±7.8x,yParameters with same suffix differ significantly.7.7±8.5xParameters with same suffix differ significantly.14.2±13.2yParameters with same suffix differ significantly.0.0002 Clr, % of Clt11.5±19.5x,yParameters with same suffix differ significantly.54.5±28.9xParameters with same suffix differ significantly.59.1±26.4yParameters with same suffix differ significantly.<0.0001β2M Clt (l/week/1.73 m2)38.3±15.9x,yParameters with same suffix differ significantly.18.1±14.3xParameters with same suffix differ significantly.20.3±11.7yParameters with same suffix differ significantly.<0.0001 Dialytic clearance (l/week/1.73 m2)28.6±6.6x,yParameters with same suffix differ significantly.5.4±3.1xParameters with same suffix differ significantly.6.5±3.2yParameters with same suffix differ significantly.<0.0001 Dialytic clearance, % of Clt82.4±24.1x,yParameters with same suffix differ significantly.51.1±37.2xParameters with same suffix differ significantly.37.3±30.1yParameters with same suffix differ significantly.0.0001 Clr (l/week/1.73 m2)9.8±15.9yParameters with same suffix differ significantly.12.7±15.116.3±11.8yParameters with same suffix differ significantly.0.001 Clr, % of Clt17.6±24.1x,yParameters with same suffix differ significantly.48.9±37.2xParameters with same suffix differ significantly.62.7±30.1yParameters with same suffix differ significantly.0.0001β2M, β2-microglobulin; ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; Cr, creatinine; Clr, renal clearance; Clt, total clearance; HD, hemodialysis; pcr, p-cresol; UN, urea nitrogen.x,yParameters with same suffix differ significantly.Parameters with same suffix differ significantly. Open table in a new tab Figure 2Total clearances in HD (n=20) and PD (n=50) patients. &P<0.01, #P<0.0005, and $P<0.0001, respectively, PD vs HD.View Large Image Figure ViewerDownload (PPT) β2M, β2-microglobulin; ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; Cr, creatinine; Clr, renal clearance; Clt, total clearance; HD, hemodialysis; pcr, p-cresol; UN, urea nitrogen. x,yParameters with same suffix differ significantly.Parameters with same suffix differ significantly. Serum concentrations are summarized in Table 3 and Figure 3. Serum concentrations of UN, creatinine, phosphate, and β2M were significantly lower in the patients on HD. pcr levels, conversely, were significantly lower in patients on PD. Similar, although somewhat more pronounced differences between HD and PD were observed in anuric patients. Significance, however, was lost for pcr (21.8±12.8 vs 16.0±12.1 mg/l, HD vs PD, P=0.3) Serum concentrations of pcr were significantly lower in CAPD patients as compared to APD patients.Table 3Mid-day (PD) and time-averaged (HD) serum concentrations in HD (n=20), APD (n=34), and CAPD (n=16) patientsHDAPDCAPDOverall ANOVAUN (mg/dl)75.2±22.7x,yParameters with same suffix differ significantly.108.8±23.2xParameters with same suffix differ significantly.109.9±27.4yParameters with same suffix differ significantly.<0.0001Cr (mg/dl)5.25±1.33x,yParameters with same suffix differ significantly.7.96±2.21xParameters with same suffix differ significantly.7.06±2.48yParameters with same suffix differ significantly.<0.0001P (mg/dl)3.12±0.97x,yParameters with same suffix differ significantly.4.97±1.40xParameters with same suffix differ significantly.4.20±0.92yParameters with same suffix differ significantly.<0.0001p-Cresol (mg/l)20.5±10.8yParameters with same suffix differ significantly.17.0±9.1xParameters with same suffix differ significantly.11.1±3.8x,yParameters with same suffix differ significantly.0.003β2M (mg/l)15.3±5.5xParameters with same suffix differ significantly.24.3±12.6xParameters with same suffix differ significantly.18.8±9.10.02ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis; PD, peritoneal dialysis.x,y Parameters with same suffix differ significantly. Open table in a new tab ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis; PD, peritoneal dialysis. Total mass removal (MR) of pcr was significantly higher in patients on HD as compared to PD. Total MR of creatinine, conversely, was significantly higher in PD (Figure 4). Significant differences between APD and CAPD were not observed (Table 4).Table 4Total mass removal (mg/week) in HD (n=20), APD (n=34), and CAPD (n=16) patientsHDAPDCAPDOverall ANOVAUN89 349±3477092 025±2742911 1649±405060.2Cr4746±2009x,yParameters with same suffix differ significantly.6522±1952xParameters with same suffix differ significantly.6918±2572yParameters with same suffix differ significantly.0.008P2356±8642739±10422790±10220.4p-Cresol351±232xParameters with same suffix differ significantly.175±108xParameters with same suffix differ significantly.214±1470.003ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis.x,y Parameters with same suffix differ significantly. Open table in a new tab ANOVA, analysis of variance; APD, automated peritoneal dialysis; CAPD, continuous ambulatory peritoneal dialysis; HD, hemodialysis. Our comparative study, comprising 20 HD and 50 PD patients, shows significantly higher total clearances of pcr and β2M during high-flux HD (Figure 2). Considering the significantly worse RRF in the HD patients, this observation is striking and clearly demonstrates that high-flux HD provides superior clearances of pcr and β2M as compared to PD. It has to be acknowledged that as we did not account for adsorption, the reported differences in dialytic clearances between both modalities most probably represent an underestimation. Studies comparing the transmembrane transport of middle molecules and protein-bound solutes in HD and PD are scarce or non-existing. Because of the high permeability of the peritoneal membrane, the continuous nature of the PD treatment, the superior preservation of RRF in this modality, and supported by clinical data, it has long been held that removal of middle molecules and protein-bound solutes is better in PD as compared to HD.19.Keshaviah P. Urea kinetic and middle molecule approaches to assessing the adequacy of hemodialysis and CAPD.Kidney Int. 1993; 43: S28-S38Google Scholar,20.Lameire N. Vanholder R. De Smet R. Uremic toxins and peritoneal dialysis.Kidney Int. 2001; 59: S292-S297Abstract Full Text PDF Scopus (47) Google Scholar It should be stressed that most of these clinical studies date from the 1970s and 1980s, a period were mainly low-flux cellulose membranes were in use.19.Keshaviah P. Urea kinetic and middle molecule approaches to assessing the adequacy of hemodialysis and CAPD.Kidney Int. 1993; 43: S28-S38Google Scholar, 20.Lameire N. Vanholder R. De Smet R. Uremic toxins and peritoneal dialysis.Kidney Int. 2001; 59: S292-S297Abstract Full Text PDF Scopus (47) Google Scholar, 21.Babb A.L. Johansen P.J. Strand M.J. et al.Bi-directional permeability of the human peritoneum to middle molecule.Proc Eur Dial Transplant Assoc. 1973; 10: 247-257PubMed Google Scholar In the present study, we provide strong evidence that with high-flux HD, the opposite is the case. Our findings thereby extend data previously reported by Keshaviah.19.Keshaviah P. Urea kinetic and middle molecule approaches to assessing the adequacy of hemodialysis and CAPD.Kidney Int. 1993; 43: S28-S38Google Scholar Serum levels of UN, phosphate, and β2M were significantly lower in HD patients, whereas serum levels of pcr were significantly lower in PD patients. Generally, serum levels of uremic retention solutes represent a balance between the rate of generation and elimination. In steady state, the total MR may represent an adequate estimation of the generation rate. This applies to all solutes assessed in the present study but β2M, which is also metabolized by the kidney to a varying extent. In agreement with previous studies, we observed similar MR of UN17.Chen T.W. Huang T.P. Liu M.C. Wang M.L. The removal index for evaluation of dialysis.Perit Dial Int. 1996; 16: 128-134PubMed Google Scholar and phosphate18.Ketteler M. Gross M.L. Ritz E. Calcification and cardiovascular problems in renal failure.Kidney Int Suppl. 2005; 94: S120-S127Abstract Full Text Full Text PDF PubMed Google Scholar in patients on PD and HD. As there are no reasons to assume a different production rate of β2M in patients on PD and HD, it seems reasonable to attribute the significantly lower serum concentrations of UN, phosphate, and β2M in HD to a more efficient removal. Obviously, β2M concentrations in HD patients reported in literature over the last two decades show a declining trend.22.Chen H.C. Guh J.Y. Lai Y.H. Tsai J.H. Serial changes of serum beta-2-microglobulin in CAPD.Perit Dial Int. 1993; 13: 238-239PubMed Google Scholar, 23.Blumberg A. Burgi W. Behavior of beta 2-microglobulin in patients with chronic renal failure undergoing hemodialysis, hemodiafiltration and continuous ambulatory peritoneal dialysis (CAPD).Clin Nephrol. 1987; 27: 245-249PubMed Google Scholar, 24.Lysaght M.J. Pollock C.A. Moran J.E. et al.Beta-2 microglobulin removal during continuous ambulatory peritoneal dialysis (CAPD).Perit Dial Int. 1989; 9: 29-35PubMed Google Scholar This is most probably a reflection of the introduction of convective therapies and the more widespread use of HD membranes with high efficiency and permeability.25.Pickett T.M. Cruickshank A. Greenwood R.N. et al.Membrane flux not biocompatibility determines beta-2-microglobulin levels in hemodialysis patients.Blood Purif. 2002; 20: 161-166Crossref PubMed Scopus (22) Google Scholar In contrast to the other retention solutes examined, pcr showed a higher generation rate in HD as compared to PD. This explains the lower serum levels of pcr in PD, despite the less efficient clearance with this modality. An increased colonic generation rate of pcr in HD may be the consequence of impaired protein assimilation26.Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Impairment of small intestinal protein assimilation in patients with end-stage renal disease: extending the malnutrition–inflammation–atherosclerosis concept.Am J Clin Nutr. 2004; 80: 1536-1543PubMed Scopus (54) Google Scholar and/or a delayed colonic transit.27.Cummings J.H. Hill M.J. Bone E.S. et al.The effect of meat protein and dietary fiber on colonic function and metabolism.Am J Clin Nutr. 1979; 32: 2094-2101PubMed Scopus (267) Google Scholar,28.Wu M.J. Chang C.S. Cheng C.H. et al.Colonic transit time in long-term dialysis patients.Am J Kidney Dis. 2004; 44: 322-327Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Differences in diet and bacterial flora should be accounted for as well. The two PD modalities were also analyzed separately (Table 2). A higher dialytic clearance of both β2M and pcr was observed in patients on CAPD as compared to APD. Statistical significances, however, was not reached. The number of exchanges was higher in patients on APD, whereas the total dwell time was longer in patients on CAPD. Kim et al.29.Kim D.J. Do J.H. Huh W. et al.Dissociation between clearances of small and middle molecules in incremental peritoneal dialysis.Perit Dial Int. 2001; 21: 462-466PubMed Google Scholar recently demonstrated that in contrast to peritoneal clearance of small molecules, such as creatinine, which is dependent on the number of exchanges, peritoneal clearance of middle molecules, such as β2M, depends mainly on the total dwell hours of PD and not on the number of exchanges of peritoneal dialysate. Although not formally tested, the same most probably holds true for the protein-bound retention solutes. As the ultrafiltration rate was slightly higher in CAPD, a higher convective transport may also have contributed to the higher clearance and significantly lower serum concentration of pcr in the latter treatment modality.30.Mistry C.D. O'Donoghue D.J. Nelson S. et al.Kinetic and clinical studies of beta-2-microglobulin in continuous ambulatory peritoneal dialysis: influence of renal and enhanced peritoneal clearances using glucose polymer.Nephrol Dial Transplant. 1990; 5: 513-519Crossref PubMed Scopus (27) Google Scholar The epuration superiority of HD over CAPD was found to be less pronounced as compared to APD. Indeed, significance between HD and CAPD was lost for pcr. It remains to be determined whether this loss of significance is owing to a lack of power or reflects a real epuration benefit of CAPD over APD. Additional studies are required to elucidate this issue. A limitation of our study is that mid-week data were extrapolated to the entire week. However, we assume that the bias related to the extrapolation is limited as patients were on the same treatment schedule for at least 4 weeks and were in stable clinical condition. The extrapolation may result in a slight underestimation of the 'true' weekly dialytic clearance in HD because of the asymmetric treatment regimen (3-2-2 day interval). As such, the 'true' difference in dialytic clearances between PD and HD may be even more pronounced. Furthermore, it should be emphasized that a rather high percentage of the PD patients (18%) were anuric at the time of inclusion. Given the importance of RRF in the overall clearance of β2M and pcr in PD patients,9.Bammens B. Evenepoel P. Verbeke K. Vanrenterghem Y. Removal of middle molecules and protein-bound solutes by peritoneal dialysis and relation with uremic symptoms.Kidney Int. 2003; 64: 2238-2243Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar caution is warranted when extrapolating the conclusions concerning the overall clearance of the latter solutes to PD populations with a better preserved RRF. Finally, we acknowledge that the kinetic behavior of β2M and pcr may be different from other members of the class of middle molecules and protein-bound solutes. These differences may be related to differences in molecular weight, strength of protein-binding, etc. Caution, therefore, is warranted when extrapolating our findings to other retention solutes. It in unclear to what extent the observed differences in solute serum level between HD and PD may affect outcome. Studies in which the mortality rates for patients undergoing HD were compared with the mortality rates for patients undergoing PD have yielded conflicting results. Recent studies lacking the limitations of these earlier studies consistently show greater relative mortality rates for PD patients with longer duration of treatment.31.Termorshuizen F. Korevaar J.C. Dekker F.W. et al.The Netherlands Cooperative Study on the Adequacy of Dialysis Study Group. Hemodialysis and peritoneal dialysis: comparison of adjusted mortality rates according to the duration of dialysis: analysis of The Netherlands Cooperative Study on the Adequacy of Dialysis.J Am Soc Nephrol. 2003; 14: 2851-2860Crossref PubMed Scopus (236) Google Scholar,32.Jaar B.G. Coresh J. Plantinga L.C. et al.Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease.Ann Intern Med. 2005; 143: 174-183Crossref PubMed Scopus (270) Google Scholar Our data suggest that besides fluid removal, blood pressure control, and generation of advanced glycation end products, also clearance of middle molecules and protein-bound solutes should be considered an explanatory variable. In the present study, we demonstrate non-equivalence of dialytic clearance delivered by PD and high-flux HD. Opposite to prevailing thoughts, we demonstrate superior dialytic clearance of water-soluble solutes, β2M, and pcr by high-flux HD as compared to PD. Although these differences, most probably are not important in the presence of substantial RRF, they may become clinically relevant when RRF falls over time.
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