New strategies in haemodiafiltration (HDF): prospective comparative analysis between on-line mixed HDF and mid-dilution HDF

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1 Nephrol Dil Trnsplnt (27) 22: doi:1.193/ndt/gfm23 Advne Aess pulition 8 Mrh 27 Originl Artile New strtegies in hemodifiltrtion (HDF): prospetive omprtive nlysis etween on-line mixed HDF nd mid-dilution HDF Annlis Feliini, Mri Alessndr Riv, Simon Zeri, Pio Ruggiero, Ann Rit Plti, Giorgio Cozzi nd Luino A. Pedrini Nephrology nd Dilysis Deprtment, Bolognini Hospitl, Serite, Bergmo, Itly Astrt Bkground. Improvement in the uremi toxiity profile otined with the pplition of onvetive nd mixed dilysis tehniques hs stimulted the development of more effiient strtegies. Our study ws prospetive rndomized evlution of the linil nd tehnil hrteristis of two new hemodifiltrtion (HDF) strtegies, mixed HDF nd mid-dilution HDF, whih hve reently een proposed with the im of inresing effiieny nd sfety with respet to the stndrd trditionl HDF infusion modes. Methods. Ten stle ptients on renl replement therpy (men ge yers) were sumitted in rndomized sequene to one mid-week session of middilution HDF nd one of mixed HDF with trnsmemrne pressure feedk ontrol. All sessions were rried out under similr operting onditions nd involved monitoring pressure within the internl dilyser omprtments nd lulting the rheologil nd hydruli indexes. Effiieny in removing ure, phosphte nd 2-mirogloulin (2-m) ws tested. Results. In mixed HDF, sfer nd more effetive flux/ pressure onditions resulted in etter preservtion of the hydruli nd solute memrne permeility (men in vivo ultrfiltrtion oeffiient vs ml/h/mmhg) nd ensured higher volume exhnge ( vs l/session, P ¼.2) nd greter effiieny in removing smll nd middle moleules (men ure lerne: vs ml/min, P ¼.28; ekt/v: vs , P ¼.36; men phosphte lerne: vs ml/min, P ¼.2; men 2-m lerne: vs ml/min, P ¼.1). Conlusions. Mixed HDF ws the most effiient tehnique in the highest rnge of sfe operting onditions. In mid-dilution HDF, high pressures Correspondene nd offprint requests to: Luino A. Pedrini, Nefrologi e Dilisi, Ospedle Bolognini, 2468 SERIATE Itly. Emil: nefrologi.serite@olognini.g.it generted inside the dilyser ompromised memrne permeility nd limited the totl infusion rte, resulting in n overll redution in solute removl. Keywords: hemodifiltrtion; memrne permeility; mid-dilution HDF; mixed HDF; phosphte; 2-mirogloulin Introdution Severl reent prospetive studies hve demonstrted tht onvetive nd mixed dilysis strtegies my indue sustined improvement in the uremi toxiity profile, y reduing the level of smll nd middle moleulr ompounds whih re reognized s risk ftors nd/or mrkers of severe uremi omplitions, suh s inflmmtion, myloidosis, seondry hyperprthyroidism nd elerted theroslerosis [1 5]. Even though not yet proven y lrge prospetive study, the omined routine use of ultrpure dilyste, highly ioomptile memrnes nd enhned solute removl y onvetion ould tully help to redue the high mortlity rte of dilysis ptients. Support for this thesis my derive from the reently pulished Euro-DOPPS Study [6], whih reported signifint 35% lower mortlity risk in ptients on hemodifiltrtion (HDF) with high volume exhnge of more thn 15 l/session, ompred with ptients on low-flux hemodilysis (HD). This stte of ffirs hs gretly enourged reserh into new nd more effiient memrnes nd dilysis strtegies. Thnks to the unlimited vilility of sterile infusion fluid whih is prepred heply y the dilysis mhine, two new on-line HDF tehniques, mixed HDF [7,8] nd mid-dilution HDF [9,1], hve reently een proposed with the im of improving the effiieny nd sfety of HDF tehnique, while t the sme time reduing the shortomings nd risks ssoited with the trditionl HDF infusion modes. Indeed, in post-dilution HDF, hemoonentrtion nd high lood visosity my use filter lotting, high Downloded from t Pennsylvni Stte University on Mrh 1, 214 ß The Author [27]. Pulished y Oxford University Press on ehlf of ERA-EDTA. All rights reserved. For Permissions, plese emil: journls.permissions@oxfordjournls.org

2 Mixed HDF nd mid-dilution HDF ompred 1673 trnsmemrne pressure (TMP) nd loss of memrne permeility, so limiting the effet of high ultrfiltrtion rtes (Q UF ) on solute removl y onvetion [7,11]. The pre-dilution mode prevents the ourrene of these negtive spets, ut t the prie of redued effiieny due to dilution of the solute onentrtion grdient ross the memrne. Both mixed HDF nd mid-dilution HDF lim etter rheologil nd hydruli onditions, nd onsequently, greter effiieny when ompred with the trditionl infusion modes. This study is omprtive nlysis of the ove spets of the two novel HDF modes. Sujets nd methods Study design Two on-line HDF modlities were ompred in this prospetive rndomized rossover study. Ptients were sumitted in rndomized sequene to one mid-week session of mixed HDF nd one of mid-dilution HDF. The study ws pproved y the lol Ethi Committee nd onduted in ordne with the priniples of the Delrtion of Helsinki nd the rules of Good Clinil Prtie. Written informed onsent ws otined from ll prtiipnts. Prospetivedefined endpoints of the omprison were the extent of overll solute removl for eh HDF modlity, nd the effiieny nd sfety of oth the dilysers nd the tehniques in terms of hydruli nd solute memrne permeility, rheologil onditions nd hydrostti pressures within the systems. Ptients Ten ptients (8 mles, 2 femles, men ge yers), who hd een on thrie weekly on-line HDF in our entre for t lest 6 months were inluded in the study. Men dilysis durtion ws months (medin vlue 36.9, rnge ). All ptients hd permnent ntive or prostheti vsulr ess ple of delivering n effetive lood flow rte (Q B eff, lood flow orreted for the effet of the negtive rteril pressure) of t lest 3 ml/min, without signifint ess reirultion (>1%). Ptients were onsidered for the study if they hd hd no ute ererl or rdio-vsulr episodes in the previous 3 months. Ptients with NYHA III- IV hert filure or with tive infetious or mlignnt disese were exluded. session. The mximl sfe limit for TMP in mixed HDF ws estlished t 3 mmhg [7]. In mid-dilution HDF, ording to the inditions of the hemodifilter mnufturer, on rehing n infusion pressure (P B mid) of 65 mmhg ment tht the infusion rte hd to e mnully nd progressively redued. The hollow-fire dilysers employed were n FX8 (Fresenius Medil Cre) in mixed HDF nd n OLpur TM MD19 (Nephros, New York, USA) in mid-dilution HDF. The min hrteristis of the filters re reported in Tle 1. The OLpur TM MD19 dilyser inludes U-shped lood pillry undle with middle infusion port t the point where lood flow reverses diretion. Blood nd dilyste flow ounter-urrent in the desending U rnh of the pillries (1.1 m 2 ), where post-dilution is performed nd o-urrently in the sending, pre-dilution U rnh (.8 m 2 ). Tretment sessions to e ompred were rried out in eh ptient using the sme lood nd dilyste flow, durtion, ntiogultion protool nd dilyste/infuste omposition. The initil infusion rte (Q R ), whih ws the sme for oth tehniques, ws set in pilot sessions where mximl tolerne to ultrfiltrtion of the ptient mhine system ws tested. Ultrpure dilyste ws produed on-line, s per routine use, using doule reverse osmosis system for wter tretment nd polysulphone ultr-filter (Disfe plus, FMC) for susequent filtrtion of the dilyste. A further stge of dilyste filtrtion ws required for prodution of the infusion fluid. In our unit, oth dilyste nd infusion fluid re heked monthly to ensure tht they re free of endotoxins (LAL test) nd meet the stndrds of miroil purity reommended y the Europen Best Prtie Guidelines. Ptients nd tretment hrteristis re summrized in Tle 1. Dt olletion nd lortory nlysis Pre-tretment lood smples were drwn immeditely fter needle insertion; post-tretment lood smples were tken from the rteril port using the slow flux tehnique. Seprte lood smples from the rteril nd vein ports were drwn 5 min fter the eginning nd 5 min efore the end of the session. During eh session, the effluent dilyste ws Tle 1. Ptients tretment hrteristis Mixed HDF Mid-dilution HDF P-vlue* n ¼ 1 n ¼ 1 Downloded from t Pennsylvni Stte University on Mrh 1, 214 Systems nd tretments A Fresenius 48 dilysis system (Fresenius Medil Cre, Bd Homurg, Germny) ws used in oth tehniques. The mhine ws equipped with five pressure trnsduers pplied t the inlet nd outlet lood nd dilyste ports of the dilysers nd t the infusion port of the mid-dilution filter. Pressure mesurements were reorded on-line y mens of dedited softwre on n externl omputer, whih lso lulted nd reorded the men TMP nd the hydruli indexes within the dilyser. A feedk system for TMP ontrol, desried in previous pulitions [12,13], ws used in mixed HDF to optimize the filtrtion frtion y selfmodulting the pre-dilution/post-dilution rtio while mintining the totl infusion rte onstnt throughout the Dry ody weight (kg) ns Body weight loss (kg) ns Q Beff (ml/min) ns Q R strt (ml/min) ns Q UF strt (ml/min) ns Q Din (ml/min) ns HD time (min) ns Memrne Helixone Polyethersulfone Surfe (m 2 ) Wll thikness (mm) 35 3 Inner dimeter (mm) 21 2 Nominl K UF (ml/h/mmhg/m 2 ) Arevitions nd definition of the prmeters re in the text (setion Methods ). Dt re mens SD. *Student s t-test for pired dt.

3 1674 A. Feliini et l. t the inlet nd outlet lood nd dilyste port, respetively nd P on (mmhg), is the men onoti pressure exerted y the plsm proteins, set y defult to onstnt vlue of 25 mmhg; olleted with proportionl pump t onstnt rte of 1 ml/h, following the prtil dilyste quntifition (DQ) method [14]. Blood nd dilyste smples were nlysed for ure, phosphte nd 2-mirogloulin (2-m) using ondutimetri, olorimetri nd immunonephelometri methods, respetively. Hemtorit (Ht) nd totl plsm protein (TP) onentrtion were mesured in rteril lood whih ws smpled 5 min fter the eginning nd 5 min efore the end of the session. The mss of solute removed during eh session (MT DQ ) ws lulted from the effluent dilyste smple (4 ml), whih ws representtive of the entire effetive volume of spent dilyste (V d ), s in: MT DQ ¼ C d V d where C d is the dilyste onentrtion of the exmined solute. The men dilyste lernes of the session (K DQ ) were lulted with the following eqution of the DQ method [14]: K DQ ¼ MT DQ lnðc f =C i Þ t ðc f C i Þ where C i nd C f re the initil nd end-session plsm wter onentrtion of the exmined solute nd t is the session durtion in minutes. Clulted s ove, MT DQ nd K DQ underestimte the tul 2-m removl, due to the mount of solute sored on the memrne. However, this systemti nd onstnt error is unlikely to ffet the results of omprison etween the different proedures in the sme ptient nd with similr polysulphone-sed dilyser memrne. The equilirted Kt/V (ekt/v) for ure ws estimted ording to the Dugirds 2nd genertion eqution [15]. Dilyser performne in middle moleule removl t different stges of the session ws evluted y lulting 2-m instntneous plsm wter lernes (K I ) t the strt nd the end of the session. The lssi equtions [16] were used to lulte plsm wter flow (Q PW ) nd K I : Q PW ¼ Q B eff 1 Ht Fp where Fp is the wter frtion of plsm; ðc rt C ven Þ C ven K I ¼ Q PW þ Q UF ð4þ C rt C rt where C rt nd C ven re the solute onentrtions t the rteril nd venous port, respetively, nd Q UF is the ultrfiltrtion rte, in millilitres per minute. On-line reording of the intr-omprtments pressures of the dilyser llowed for lultion of the instntneous vlues for the men TMP (mmhg), for the Resistne Index (RI, mmhg/ml/min), used to evlute the pressure/flow onditions of the lood omprtment, nd for the in vivo ultrfiltrtion oeffiients of the dilyser memrne (K UF, ml/h/mmhg of TMP/m 2 ), whih ws used s proxy for hnges in the hydruli permeility of the dilyser during the sessions. The following equtions were used: men TMP ¼ :5 ðp ½ Bin þ P B out Þ ðp Din þ P D out ÞŠ P on ð5þ where P Bin, P B out, P Din nd P D out re the pressures (mmhg) ð1þ ð2þ ð3þ RI ¼ ðp Bin P B out Þ Q Bin where Q Bin is the flow (ml/min) t the inlet lood port; Q UF K UF ¼ men TMP=m 2 Sttistil nlysis The desriptive nlysis ws sed on the men SD vlues of ontinuous normlly distriuted vriles. The effets of the two proedures on prmeters of tretment effiieny (K DQ, ure Kt/V nd MT DQ ) were ompred with the Student s t-test for pired dt. A P-vlue <.5 ws onsidered signifint. Results Hydruli ptterns Figure 1 shows the pressure profiles t the inlet nd outlet lood nd dilyste omprtments of the dilyser, s reorded minute y minute throughout the two experimentl proedures y the omputer onneted to the dilysis mhine. Men TMP for eh session ws lulted y elorting the pressure vlues mesured t the four points of the extrorporel iruit using eqution (5) nd the softwre. The trend is shown in Figure 2, where the line lelled with the letter t represents the TMP vlue displyed on the mhine monitor. This vlue, here defined s two-point TMP, is lulted y the mhine s the differene of two point-pressures reorded ehind the lood nd dilyste outlet ports. For tehnil resons (lk of speifi pressure sensors t the inlet lood nd dilyste ports) Fresenius 48 nd Gmro systems use this two-point TMP s proxy for the tul men TMP, on the sis of n eqution relting the two mesures, whih is not otinle from the mnufturers. The two-point TMP lulted s ove often provides n inurte estimte of the true men TMP. Over- or under-estimtion depends on the opertionl onditions. Prtiulrly in the se of mid-dilution HDF, the two-point TMP gretly underestimtes the tul TMP t different points of the dilyser, ove ll t the initil nd middle prt of the post-dilution setion (Figure 2B). Widely different ptterns were estlished in the two proedures. In mixed HDF, pressure in lood omprtment ws kept sustntilly onstnt for the durtion of the session s n effet of the feedk devie-ontrolling TMP. In generl, loss of hydruli memrne permeility ours minly in the first 15 2 min of n HDF session, s onsequene of hemoonentrtion nd protein lyer formtion on the memrne surfe. This then requires the TMP to e progressively inresed, sometimes up to dngerous vlues, in order to mintin the ð6þ ð7þ Downloded from t Pennsylvni Stte University on Mrh 1, 214

4 Mixed HDF nd mid-dilution HDF ompred 1675 A P, mmhg A TMP, mmhg d t 2 2 t progrmmed ultrfiltrtion. In mixed HDF, s in the present experimentl setting, ny TMP inrese ws prevented y the feedk TMP regultion through repeted smll shifts of infusion fluid from the postdilution to the pre-dilution site with no effet on the totl infusion nd ultrfiltrtion rte (Figures 2A nd 3A). On the ontrry, in mid-dilution HDF, very high pressure vlues were reorded right from the eginning of the sessions oth t the inlet lood omprtment nd long its first prt, the post-dilution setion, up to the infusion site. As sessions progressed, further inrese ourred nd inlet lood pressure (P Bin ) nd infusion pressure (P mid) rose to dngerous levels despite ttempts to redue this effet with repeted mnul redution of the totl infusion rte (Figure 3B). Men TMP vlues hieved in the post-dilution setion B TMP, mmhg Fig. 2. Men trns-memrne pressure (TMP) profile with 95% CI (thin grey lines) of the two experimentl proedures, lulted from the pressure reorded t the inlet nd outlet lood nd dilyste omprtments. (A) Mixed HDF: line, men TMP. (B) Mid-dilution HDF: lines nd represent the men TMP of the first nd seond setion of the dilyser where, respetively, post-dilution nd pre-dilution our. Line t were the two-point TMP ppering on the disply of the mhine (explntion in the text). B P, mmhg e d Fig. 1. Hydruli pressure profile t the inlet nd outlet lood nd dilyste omprtments of the dilysers (P Bin, P B out, P Din, P D out, respetively), s reorded during the two experimentl proedures. (A) Mixed HDF; (B) mid-dilution HDF. Line, P Bin ; line, P B out ; line, P Din ; line d, P D out. Line e, P Bmid, i.e. pressure t the infusion port of the dilyser in the mid-dilution tehnique. re shown in Figure 2B nd the filtrtion pressure t different points long the pillries is shemtilly depited in Figure 4. The totl volume exhnged during the mid-dilution HDF sessions ws signifintly lower thn in mixed HDF sessions ( vs l, P ¼.2), s n effet of the neessry redution of the infusion rte during the former proedure. The resistne index during the two experimentl proedures, depited in Figure 5A, showed more fvourle flux/pressure rtio within the dilyser in mixed HDF. The trend of the in vivo ultrfiltrtion oeffiient of the memrnes (Figure 5B), fter the expeted initil redution in oth proedures, demonstrted tht hydruli memrne permeility ws etter preserved in the pre-dilution setion of the Downloded from t Pennsylvni Stte University on Mrh 1, 214

5 1676 A. Feliini et l. A 2 B Q R, ml/min 12 8 Q R, ml/min MD19 dilyser. It deteriorted during mixed HDF nd even more during mid-dilution HDF in the postdilution setion, ut only in the ltter se were very high TMP vlues required to preserve the plnned ultrfiltrtion flow. Effiieny of the proedures Bseline nd end-session ptient prmeters of the two experimentl proedures re reported in Tle 2 nd it n e seen tht there ws signifint differene only in initil nd finl 2-m levels. Mixed HDF proved to e more effiient in removing smll nd middle-sized solutes. As reported in Tle 3, ure lerne K DQ nd equilirted Kt/V were signifintly higher thn in mid-dilution HDF, while the differene in terms of phosphte removl, even if linilly relevnt, did not hieve sttistil signifine, proly s onsequene of the smll numer nd dispersion of dt. Defined superiority ws shown regrding 2-m removl. The men lerne K DQ nd the instntneous 2-m dilysers lernes K I were signifintly higher in mixed HDF ompred with middilution HDF, oth t the eginning nd t the end of the session (Tle 3). The expeted derese in K I towrd the end of the session ws less relevnt in mixed HDF (16.7%) thn in mid-dilution HDF (38%), onfirming more effiient preservtion of the solute memrne permeility in the former proedure. Disussion Fig. 3. Infusion rtes during the two experimentl proedures. In mixed HDF (A) onstnt totl infusion rte (Q R ) of ml/min (line ) ws mintined y djusting the pre/post-dilution infusion rtio under TMP feedk ontrol. During the session, TMP vlues whih exeeded the upper limit of 3 mmhg were redued y shifts of infusion fluid from post-dilution (line ) to pre-dilution (line ). Pre-dilution nd post-dilution rtes were nd ml/min t the strt nd nd 57 2 ml/min t the end of the sessions. In middilution HDF (B), exessive PBmid vlues imposed Q R redution from ml/min (strt-session) to ml/min (end-session). P, mmhg Arteril port Mid-dilution port Venous port PB PD Fig. 4. Shemti representtion of the men filtrtion pressure (TMP) ting t different points long the length of the pillries (from the rteril port to the venous port), expressed s men vlue of the mid-dilution HDF sessions. Men filtrtion pressure ws lulted from the differenes of the pressures in lood (P) nd dilyste (Pd) omprtments, ounting for P on nd represented with the outlined vlues. In this study, mixed HDF nd mid-dilution HDF were ompred in the sme ptients under mthing operting onditions whih inluded presried infusion nd ultrfiltrtion rtes. Effiieny in removl of tested solutes ws definitely higher in mixed HDF where there ws sttistilly signifint higher lerne of low (ure) nd middle moleulr weight solutes (2-mirogloulin). In line with other studies [17], phosphte removl ws in the high rnge with no sttistil differene etween the two tehniques, even though the differene ould e of linil relevne, lso in onsidertion tht pre-dilysis phosphte onentrtion ws well within the norml rnge, whih ws proly n effet of the high effiieny tretment prior to the study. Dt otined y mens of the pressure/flux monitoring system used in this study provided plusile explntion of these results. In mid-dilution HDF, very high hydruli pressures were reorded for the entire durtion of eh session within the lood omprtment of the dilyser, espeilly in its first setion where post-dilution tkes ple. The overll surfe re of pillries in this setion is reltively low (1.1 m 2 ) nd s depited in Figure 5, this my Downloded from t Pennsylvni Stte University on Mrh 1, 214

6 Mixed HDF nd mid-dilution HDF ompred 1677 A 1.4 B RI, mmhg/ml/min KUF, ml/h/mmhg/m Fig. 5. Behviour of the resistne index RI (A) nd the in vivo ultrfiltrtion oeffiient of the dilyser memrne K UF (B), s lulted from equtions 6 nd 7, respetively nd reorded on-line during mixed HDF (line ) nd mid-dilution HDF (post-dilution, line ; predilution, line ). Tle 2. Bseline nd end-session ptient prmeters. Tle 3. Effiieny of the experimentl proedures Mixed HDF Mid-dilution HDF P-vlue* n ¼ 1 n ¼ 1 Ure Mss trnsfer (g) ns K DQ (ml/min) ekt/v Phosphte Mss trnsfer (mg) ns K DQ (ml/min) ns 2-mirogloulin Mss trnsfer (mg) <.1 K DQ (ml/min) <.1 K I strt session, <.1 (ml/min) K I end session (ml/min) Dt re mens SD. *Student s t-test for pired dt. Mixed HDF Mid-dilution HDF P-vlue* n ¼ 1 n ¼ 1 Ure (mg/dl) Strt ns End ns Phosphte (mg/dl) Strt ns End ns 2-mirogloulin (mg/l) Strt End Hemtorit (%) Strt ns End ns Totl protein (g/dl) Strt ns End ns Dt re mens SD. *Student s t-test for pired dt. 8 6 rete high resistne to the lood entering the dilyser nd eoming progressively more onentrted long the fires. Resistne is further inresed y the infusion flow t the middle port of the dilyser, in spite of the pressure drop used y ultrfiltrtion. Very high TMP vlues re set y the mhine s volumetri ultrfiltrtion ontrol in n ttempt to ensure the plnned ultrfiltrtion nd s onsequene, normlly high pressures re lso generted in the dilyste omprtment. As n e seen in Figure 4, sustntilly different pressure nd flux onditions were oserved in the seond setion of the mid-dilution dilyser, this eing n effet of the mssive dilution of lood t the middle port. Under these irumstnes, non-homogeneous distriution of the ultrfiltrtion flow is likely to tke ple, mostly in the smll post-dilution setion where there is very high filtrtion pressure. It is well known tht extremely high filtrtion pressures, esides reting risk of pillry dmge nd rupture, lso use signifint deteriortion of the memrne due to the progressive depositing nd thikening of the protein lyer on its surfe leding to loss of hydruli nd solute permeility. In ddition, in the seond prt of the dilyser, the effiieny of solute removl is likely to e signifintly ompromised y the mssive dilution of lood, reduing the solute onentrtion ville for diffusion nd onvetion ross the memrne, nd y the o-urrent lood-dilyste flows, further reduing the grdient for solute diffusion into the dilyste flow. The ove onsidertions provide n explntion of why, in the present study, we were unle to mintin the plnned initil men infusion rte of pproximtely 1 l/h during the session, even when we tolerted exessive internl pressure within the lood omprtment, in respet of the referene limit (P inf < 65 mmhg) suggested y the produer. However, in our opinion, this limit is neither dvisle nor sfe for pplitions in routine linil setting. Downloded from t Pennsylvni Stte University on Mrh 1, 214

7 1678 A. Feliini et l. Indeed, even elow this vlue, dngerous trnsmemrne nd lood inlet pressure n result, s shown in our study. Neither is the TMP ontrol lrm displyed on the mhine monitor (the two-point TMP) of ny help s, for the reson explined ove, it gretly underestimtes the tul pressure t different points of the dilyser. This prolem ws pprently disregrded in the min report pulished on mid-dilution HDF [9]. In this study, in whih exellent results in terms of effiieny re reported, the sfety protool is provided for redution of the infusion rte of 2 ml/min if TMP rose ove 4 mmhg. Internl pressure monitoring ws not performed ut, ording to our results, suh two-point TMP vlues neessrily imply n internl pressure regimen whih is even higher thn tht oserved in our study. In tht setting, ogultion of the extrorporel lood iruit in one mid-dilution HDF session [9] nd sustined lumin lekge were preditle omplitions. Mixed HDF is n experimentl HDF tehnique whih hs een performed in our entre on modified 48 Fresenius system sine 1998 [7,8]. The si onept is tht splitting the infusion etween pre- nd post-filter gurntees the est possile rheologil nd hydruli onditions within the dilyser t the highest fluid exhnge rte nd with the most solute removl y onvetion. Applition of TMP feedk ontrol system nd implementtion of the new 58 Fresenius mhine hs gretly improved the performne nd sfety of this tehnique. The TMP feedk ontrol ts y modulting the rtio etween pre- nd postdilution in order to grdully hieve nd then mintin n optiml nd sfe TMP vlue for the entire session. This ensures mximl onvetion while etter preserving dilyser memrne permeility. The hrteristis nd linil results of mixed HDF hve lredy een reported in previous pulitions [12,13,18]. The resistne index nd in vivo ultrfiltrtion oeffiient monitored throughout the sessions nd shown in Figure 5 lso demonstrted tht the hydruli hrteristis of the dilyser re etter preserved in mixed HDF. This is proly the min explntory ftor for the ler differene in effiieny etween the two strtegies exmined in this study. In ft, for this reson, in mixed HDF it ws possile to hieve greter exhnge volume nd thus, higher ultrfiltrtion flux, whih resulted in signifintly higher onvetive removl of 2-mirogloulin. Our view is supported not only y our experiene [18], ut lso y the results of study in pre-dilution HDF [19], whih showed tht higher 2-mirogloulin removl nd miniml lumin loss resulted from profiled filtrtion mode, plnned to grdully inrese the ultrfiltrtion rte from n initil low level. In mid-dilution HDF, the in vivo ultrfiltrtion oeffiient showed eptle vlues only in the seond omprtment of the dilyser, where sfer pressure/flux onditions ourred, ut only s result of extreme nd unfvourle lood dilution. The sme ntiogultion therpy ws pplied during the sessions of oth tehniques in the study, sed on the ft tht pulished works on mid-dilution HDF do not indite ny neessity to modify the heprin dose [1]. However, in onsidertion of the high internl pressure oserved in the mid-dilution dilyser nd the ft tht mjor pro-ogultory tivity my result in the presene of very high ultrfiltrtion flux [2], we onduted dditionl tril sessions with 5% inrese of heprin. Results in terms of pressure, flux nd effiieny did not hnge in the tested ptients. In onlusion, oth tehniques demonstrted signifint removl of smll nd medium sized uremi ompounds. However, in the se of mid-dilution HDF, these results were otined only y tolerting unsfe opertionl onditions in terms of hydruli pressure within the dilyser. Lk of n effiient pressure ontrol system is prtiulrly worrisome for sfety in routine linil pplitions. Improvements in this tehnique should inlude reonsidering the dilyser geometry nd surfe. The superior performne of mixed HDF is sed fundmentlly on the pity to etter preserve the hydruli nd solute memrne permeility nd thus, to ensure mximl removl y onvetion of middle moleulr toxi ompounds, thnks to the effiient nd sfe flux/pressure onditions whih re gurnteed y the strit ontrol of the TMP feedk devie. This devie, implemented on new dilysis mhine, works inexpensively nd utomtilly dpts the opertionl onditions to the ptient nd dilyser prmeters (lood flow, hemtorit, ogultion sttus, surfe nd memrne permeility). Aknowledgements. Prt of this study hs een presented s orl free ommunition t the 52nd Annul Meeting of the ASAIO in Chigo, USA, 26, nd t the XLIII ERA-EDTA Congress in Glsgow, GB, 26. The study ws supported y n unlimited grnt from Fondzione Orizzonte Onlus (non-profit Orgniztion), Vino Cremso, Itly. The results presented in this rtile hve not een pulished previously in whole or prt, exept in strt formt. Conflit of interest sttement. L.A.P. hs, presently, temporry onsultny greement with Fresenius Medil Cre, Bd Homurg, Germny. The other uthors delre no onflit of interest. Referenes 1. Ayli M, Ayli D, Azk A et l. The effet of high-flux hemodilysis on dilysis-ssoited myloidosis. Ren Fil 25; 27: Beerenhout CH, Luik AJ, Jeuken-Mertens SG et l. Predilution on-line hemofiltrtion vs low-flux hemodilysis: rndomized prospetive study. Nephrol Dil Trnsplnt 25; 2: Lotelli F, Mrelli D, Conte F et l. Comprison of mortlity in ESRD ptients on onvetive nd diffusive extrorporel tretments. 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