Optimization of mid-dilution haemodiafiltration: technique and performance

Transcription

1 2816 L. A. Pedrini et l. 15. Winkelmyer WC, Levin R, Setoguchi S. Associtions of kidney function with crdiovsculr mediction use fter myocrdil infrction. Clin J Am Soc Nephrol 28; 3: Young EW, Goodkin DA, Mpes DL et l. The dilysis outcomes nd prctice ptterns study (DOPPS): n interntionl hemodilysis study. Kidney Int 2; 57(Suppl 74): S74 S Pisoni RL, Gillespie BW, Dickinson DM et l. The dilysis outcomes nd prctice ptterns study (DOPPS): design, dt elements, nd methodology. Am J Kidney Dis 24; 44: Klein JP, Moescherger ML. Survivl Anlysis Techniques for Censored nd Truncted Dt. New York: Springer, 1997, Newhouse JP, McClelln M. Econometrics in outcomes reserch: the use of instrumentl vriles. Annu Rev Pulic Helth 1998; 19: Brookhrt MA, Wng PS, Solomon DH et l. Evluting short-term drug effects using physicin-specific prescriing preference s n instrumentl vrile. Epidemiology 26; 17: Stukel TA, Fisher ES, Wennerg DE et l. Anlysis of oservtionl studies in the presence of tretment selection is: effects of invsive crdic mngement on AMI survivl using propensity score nd instrumentl vrile methods. JAMA 27; 297: Crr AA, Kowey PR, Devereux RB et l. Hospitliztions for new hert filure mong sujects with dietes mellitus in the RENAAL nd LIFE studies. Am J Crdiol 25; 96: Ppdemetriou V, Frsng C, Elmfeldt D et l. Stroke prevention with the ngiotensin II type 1-receptor locker cndesrtn in elderly ptients with isolted systolic hypertension: the Study on Cognition nd Prognosis in the Elderly (SCOPE). J Am Coll Crdiol 24; 44: Young JB, Dunlp ME, Pfeffer MA et l. Mortlity nd moridity reduction with cndesrtn in ptients with chronic hert filure nd left ventriculr systolic dysfunction: results of the CHARM low-left ventriculr ejection frction trils. Circultion 24;11: Suzuki H, Knno Y. Effects of cndesrtn on crdiovsculr outcomes in Jpnese hypertensive ptients. Hypertens Res 25; 28: Cice G, Ferrr L, D Andre A et l. Crvedilol increses two-yer survivl in dilysis ptients with dilted crdiomyopthy: prospective, plceo-controlled tril. J Am Coll Crdiol 23; x41: Griffith TF, Chu BS, Allen AS et l. Chrcteristics of treted hypertension in incident hemodilysis nd peritonel dilysis ptients. Am J Kidney Dis 23; 42: Psty BM, Smith NL, Siscovick DS et l. Helth outcomes ssocited with ntihypertensive therpies used s first-line gents. A systemtic review nd met-nlysis. JAMA 1997; 277: Yusuf S, Sleight P, Pogue J et l. The Hert Outcomes Prevention Evlution Study Investigtors. Effects of n ngiotensin-convertingenzyme inhiitor, rmipril, on crdiovsculr events in high-risk ptients. N Engl J Med 2; 342: Znnd F, Kessler M, Lehert P et l. Prevention of crdiovsculr events in end-stge renl disese: results of rndomized tril of fosinopril nd implictions for future studies. Kidney Int 26; 7: Kowey PR, Dickson TZ, Zhng Z et l. Losrtn nd end-orgn protection lessons from the RENAAL study. Clin Crdiol 25; 28: Srkr SR, Kotnko P, Levin NW. Interdilytic weight gin: implictions in hemodilysis ptients. Semin Dil 26; 19: Sntos SF, Peixoto AJ. Revisiting the dilyste sodium prescription s tool for etter lood pressure nd interdilytic weight gin mngement in hemodilysis ptients. Clin J Am Soc Nephrol 28; 3: Received for puliction: ; Accepted in revised form: Nephrol Dil Trnsplnt (29) 24: doi: 1.193/ndt/gfp27 Advnce Access puliction 6 My 29 Optimiztion of mid-dilution hemodifiltrtion: technique nd performnce Lucino A. Pedrini, Annlis Felicini, Simon Zeri, Giorgio Cozzi nd Pio Ruggiero Nephrology nd Dilysis Division, Fondzione Orizzonte Bolognini Hospitl, Serite, Bergmo, Itly Correspondence nd offprint requests to: Lucino A. Pedrini; E-mil: nefrologi.serite@olognini.g.it Astrct Bckground. Mid-dilution hemodifiltrtion (MD-HDF), reported s highly efficient convective-mixed technique, hs demonstrted serious drwcks in reltion to the high pressure originting inside the lood comprtment of the filter during clinicl ppliction. This rndomized crossover design study ws plnned to optimize the efficiency of the MD-HDF technique while reducing its inherent risks. Methods. Fifteen ptients on RRT were sumitted in rndom sequence to stndrd nd reverse MD-HDF under similr operting conditions. Efficiency in solute removl ws evluted y mesuring ure (U), phosphte (P) nd et2- microgloulin (β2-m), men dilyste clernces (K DQ ) nd ekt/v. Blood nd dilyste comprtment pressures were monitored on-line during the sessions, nd instntneous hydrulic nd memrne permeility indexes were clculted. Results. During stndrd MD-HDF sessions, unlike with reverse MD-HDF, excessive lood inlet nd trnsmemrne pressure prevented the plnned infusion from eing mintined. Resistnce index nd memrne permeility to C The Author [29]. Pulished y Oxford University Press on ehlf of ERA-EDTA. All rights reserved. For Permissions, plese e-mil: journls.permissions@oxfordjournls.org

2 Mid-dilution HDF 2817 wter nd middle molecules sustntilly improved with reverse MD-HDF. This resulted in higher β2-m removl (221.3 ± 81.3 versus ± 65.5 mg/session, P =.7). Phosphte removl ws comprle, while U removl ws greter with stndrd MD-HDF (K DQ 272 ± 35 versus 252 ± 29 ml/min, P =.2; ekt/v 1.63 ±.23 versus 1.49 ±.17, P =.5). Conclusions. This study demonstrted the ility of MD- HDF to remove significnt mounts of medium-sized uremic compounds nd phosphte, ut sfe rheologic nd hydrulic conditions were only mintined y crrying out tretments with the dilyser used in reverse configurtion. For this purpose, the lrger MD-22 dilyser ensured etter tolernce together with higher middle molecules clernce, even though smll molecule removl ws slightly worsened. The results of this study my provide some insight into the complex interctions etween pressures nd flux within the originl structure of MD-dilysers nd help optimize the clinicl ppliction of the technique nd reduce its risks. Keywords: et2-microgloulin; convective tretments; hemodifiltrtion; mid-dilution HDF; trnsmemrne pressure Introduction Convective dilysis strtegies with synthetic high-flux memrnes my induce sustntil improvement in the uremic toxicity profile y reducing the level of smll nd middle moleculr compounds, some of which re recognized s pthogenic fctors of the more common long-term uremic complictions [1 6]. A link etween enhnced solute removl nd survivl on dilysis, even if not definitely estlished, ws suggested y the Euro DOPPS Study [7], which reported significnt 35% lower mortlity risk in ptients on high-efficiency hemodifiltrtion (HDF, volume exchnge l), compred to low- nd high-flux hemodilysis (HD). Among the recently proposed techniques imed t incresing convective solute trnsport, mid-dilution HDF (MD-HDF) hs een climed to e of greter efficiency when compred to trditionl pre- or post-dilution infusion modes in HDF [8,9]. However, when pplied s proposed in the originl study, MD-HDF often crries with it serious risks. Indeed, considerly high trnsmemrne pressure (TMP) of 1 mmhg in the post-dilution section of the filter ws necessry to chieve the plnned ultrfiltrtion of out 1 l/h [1]. This finding ws confirmed y other uthors [11], who succeeded in reducing the internl dilyser pressure regimen y reversing the configurtion of the lood tuing (reverse MD-HDF), i.e. connecting the rteril line to the venous port of the MD-19 dilyser nd vice vers, ut t the cost of sustntil reduction in the infusion rte from 1 to 6 l/h nd less efficient smll molecule removl. Susequently, the possiility of using higher volume exchnge under sfer hydrulic conditions in MD- HDF ws preliminrily shown in few ptients with the use of filter with lrger overll surfce re (OLpur TM MD-22, 2.2 m 2 ) in stndrd MD-HDF configurtion [12]. Even if not yet confirmed y systemtic study, this finding suggests tht the risk of high TMP in stndrd MD-HDF with the MD-19 dilyser my e reduced with the use of the lrger MD-22 filter. On the other hnd, more sustntil dvntges in sfety hve een otined y reversing the configurtion of oth MD-19 nd MD-22 dilysers [11,12]. This might e rther surprising, s the surfce of the cpillries of the post-dilution section, where the highest resistnce to flux is generted, is smller in reverse thn in stndrd MD-HDF, nd s consequence, higher hydrulic pressure should e found in reverse configurtion. The ville experience is sufficient neither to fully understnd the complex reltionship etween pressure nd flux in this technique nor to distinguish the respective roles of dilyser configurtion nd its surfce re in influencing the performnce of reverse MD-HDF in terms of solute removl, rheology nd hydrulics. Thus, while plnning this crossover comprison study etween stndrd nd reverse MD-HDF, we selected two dilysers of different overll memrne surfces (MD-19 for stndrd nd MD-22 for reverse MD-HDF), ut with very similr re of cpillries devoted to post-dilution (see Figure 1), in order to mtch the size of the filter section where post-dilution occurs nd the most criticl pressures re generted. Possily, y minimizing the effect of this vrile, the differences etween the configurtions could e more clerly reveled, with the finl im of defining correct procedure for the clinicl ppliction of MD-HDF nd of evluting its true cpcity to sfely remove smll- nd middle-sized uremic solutes. Sujects nd methods Study design In this prospective crossover study, reverse MD-HDF with the lrger MD- 22 hemodifilter ws evluted y compring it with stndrd MD- HDF performed with the MD-19 dilyser, s originlly proposed [8,9]. This comprison ws etween dilysers with the sme memrne nd with similr surfce re of the cpillries devoted to post-dilution (see Figure 1), so ensuring tht the difference in the surfce would hve no significnt impct on the evlution of the effects of the dilyser configurtion. Ptients were sumitted rndomly to mid-week session of oth tretments. Defined end-points of the comprison were the extent of overll solute removl nd the efficiency nd sfety of oth technique configurtions in terms of hydrulic nd solute memrne permeility, rheologicl conditions nd hydrosttic pressures within the system. The study ws pproved y the locl Ethics Committee. Written informed consent ws otined from ll prticipnts. Ptients Fifteen ptients (12 mles, 3 femles) who were stle on three times weekly renl replcement therpy in our centre for t lest 6 months were included in the study. The men ge ws 67.3 ± 8.7 yers, men dilysis durtion ws 44.1 ± 2.8 months (rnge ) nd men dry ody weight ws 76.9 ± 14 kg. All ptients hd permnent ntive or prosthetic vsculr ccess cple of delivering n effective lood flow rte (Q Beff, lood flow corrected for the effect of the negtive rteril pressure) of t lest ml/min, without significnt ccess recircultion (<1%). System nd tretments All experimentl sessions were performed with Fresenius 8 dilysis system (Fresenius Medicl Cre, Bd Homurg, Germny), equipped with five pressure trnsducers tht continuously mesured the hydrulic pressure in mmhg t the inlet nd outlet lood nd dilyste ports of the dilysers (P B in, P B out, P D in nd P D out, respectively) nd t the mid-dilution infusion port (P inf ). Aout signls/min were trnsmitted from ech proe to n externl computer tht filtered, uffered nd

3 2818 L. A. Pedrini et l. Fig. 1. OLpur TM dilysers for MD-HDF. Pnel A: stndrd configurtion with MD-19. Blood flows counter-currently with dilyste in the nnulr region of the fire undle (1.1 m 2 ), where post-dilution occurs, reverses its direction t the infusion site where it mixes with sustitution fluid, then flows co-currently with dilyste through the core region of the fire undle (.8 m 2 ). Pnel B: reverse MD-HDF with the MD-22 dilyser. Post-dilution occurs in the core region of the fire undle (1. m 2 ) through which lood first flows, then pre-dilution is performed in the nnulr region (1.2 m 2 ) with co-current dilyste flow. verged mesured pressure vlues for ech minute of the session y mens of dedicted softwre progrm. This produced series of Excel files t the end of ech experimentl session tht contined the minute-y-minute vlues of ll pressures nd fluxes (lood, dilyste, infuste nd ultrfiltrte) occurring within the dilyser comprtments during the session. More detiled explntion of the system ws reported in previous work [1]. The hollow-fire filters employed were the OLpur TM MD-19 nd MD-22 (Nephros, NeY, USA) in the originl (stndrd) nd in reverse configurtions, respectively. Both dilysers include cpillry undle with two lood comprtments in series in U configurtion nd n infusion port for sustitution fluid in etween, where lood flow reverses its direction. In the common dilyste comprtment, flow is counter-current for one of the seril lood comprtments nd co-current for the other (see Figure 1). Tretment sessions to e compred were crried out on ech ptient using similr lood nd dilyste flow (Q B nd Q D, respectively), ultrfiltrtion rte (Q UF ), session durtion nd dilyste/infuste composition (see Tle 1). The initil infusion rte (Q inf ), which ws dpted individully to the ptient s lood flow rte, ws lso the sme for oth techniques. According to the indictions of the hemodifilter mnufcturer, Q inf hd to e mnully nd progressively reduced on reching n infusion pressure (P inf ) of 65 mmhg. The nticogultion protocol ws dpted individully in preliminry sessions in order to chieve men ctivted clotting time etween 21% of the sl vlue fter the initil unfrctionted heprin olus nd 15% under continuous heprin dministrtion. Ultrpure dilyste ws produced on-line, s per routine use, using doule reverse osmosis system for wter tretment nd polysulfone ultrfilter (Disfe plus, FMC) for susequent filtrtion of the dilyste. A further stge of dilyste filtrtion ws required for production of the infusion fluid. Both dilyste nd infusion fluid were free of endotoxins (negtive LAL test) nd met the stndrds of microil purity recommended y the Europen Best Prctice Guidelines [13]. Dt collection nd lortory nlysis Pre-tretment lood smples were drwn immeditely fter needle insertion, nd post-tretment lood smples were tken from the rteril port using the slow-flux technique. Seprte lood smples from the rteril Tle 1. Ptient nd tretment chrcteristics Stndrd MD- Reverse MD- HDF (MD-19) HDF (MD-22) (n = 15) (n = 15) P-vlue Dilysers Memrne Polyethersulfone Polyethersulfone Surfce (m 2 ) Annulr/core 1.1/.8 1.2/1. region (m 2 ) Wll thickness 3 (µm) Inner dimeter 2 (µm) Nominl K UF 47.4 (ml/h/mmhg/m 2 ) Flux (ml/min) Q Beff 375 ± ± 3 n.s. Q Inf strt 166 ± ± 2 n.s. Q UF strt 175 ± ± 5 n.s. Q Din 593 ± 8 66 ± 5 n.s. Body weight, strt 76.6 ± ± 15. n.s. session (kg) Body weight loss (kg) 2. ± ±.9 n.s. Tretment time (min) 224 ± ± 22 n.s. Arevitions nd definition of the prmeters re in the text (see the Sujects nd methods section). Dt re presented s mens ± SD. Student s t-test for pired dt. A proility vlue of <.5 ws considered significnt.

4 Mid-dilution HDF 2819 nd vein ports were drwn 5 min fter the eginning nd 5 min efore the end of the session. During ech session, the effluent dilyste ws collected with proportionl pump t constnt rte of 1 ml/h, following the prtil dilyste quntifiction (DQ) method [14]. The lood nd dilyste smples were nlysed for ure, phosphte nd et2-microgloulin (β2-m) using conductimetric, colorimetric nd immunonephelometric methods, respectively. Hemtocrit (Hct) nd totl plsm protein (TP) concentrtions in rteril lood were mesured t the eginning nd end of the session. The mss of solute removed during ech session (MTDQ) ws clculted from the effluent dilyste smple ( 4 ml), which ws representtive of the entire effective volume of spent dilyste (V d ), s given in MT DQ = C d V d (1) where C d is the dilyste concentrtion of the exmined solute. The men dilyste clernces of the session (KDQ) were clculted with the following eqution of the DQ method [14]: K DQ = [MT DQ ln(c f /C i )]/[t (C f C i )] (2) where C i nd C f re the initil nd end-session plsm wter concentrtions of the exmined solute nd t is the session durtion in minutes. The equilirted Kt/V (ekt/v) for ure ws estimted ccording to the Dugirds second-genertion equtions [15]. Dilyser performnce in middle molecule removl t different times of the session ws evluted y clculting β2-m instntneous plsm wter clernces (K i )tthe strt nd the end of the session. The clssic equtions [16] were used to clculte plsm wter flow (Q PW )ndk i : Q PW = Q Beff (1 H ct /1)F p (3) where F p is the wter frction of plsm; K i = Q PW (C rt C ven )/C rt + Q UF C ven /C rt (4) where C rt nd C ven re the solute concentrtions t the rteril nd venous port, respectively, nd Q UF is the ultrfiltrtion rte (ml/min). On-line recording of pressures nd fluxes otined s explined ove enled the clcultion of instntneous vlues for the TMP proximlly to the entry nd exit of oth lood comprtments s the difference etween lood nd dilyste pressure ccording to the generl eqution: P B P D P onc (5) where P B nd P D re the hydrulic pressures (mmhg) in the lood nd dilyste comprtments t the mesurement point nd P onc (mmhg) is the men oncotic pressure exerted y the plsm proteins, which ws set y defult t constnt vlue of 25 mmhg ecuse it ws impossile to otin lood smples from the mid-dilution port of the MD dilysers during tretment. Moreover, the prticulr construction of these dilysers with unique dilyste nd two lood comprtments prevented us from scertining the exct rte of ultrfiltrtion tht occurred in ech lood pth nd thus from deriving vlue for protein concentrtion from chnges in plsm flow rte due to ultrfiltrtion. The sme recorded dt were used to clculte the instntneous pressure drop within the two lood comprtments (P B in P B out ), the resistnce index (R I, mmhg/ml/min) ws used to evlute the pressure/flow conditions of the lood comprtments nd the in vivo ultrfiltrtion coefficients of the dilyser memrne (K UF, ml/h/mmhg of TMP/m 2 )were used s proxy for chnges in the hydrulic permeility of the dilyser during the sessions. The following equtions were pplied: R I = (P Bin P B out )/Q Bin (6) where Q B in is the flow (ml/min) t the inlet lood port; K UF = Q UF /men TMP/m 2. (7) Instntneous vlues of ech of the ove-mesured nd -clculted prmeters were stored in the Excel dt files nd used for sttisticl nlysis nd to descrie their trend during ech session. Sttisticl nlysis The descriptive nlysis ws sed on the men ± SD vlues of continuous normlly distriuted vriles. The effects of the two procedures on prmeters of tretment efficiency (K I, KDQ, ure Kt/V, nd MT DQ ) were compred with Student s t-test for pired dt. A proility vlue of <.5 ws considered significnt. Results All ptients completed the experimentl sessions of oth tretments with no technicl prolems. In prticulr, there were no occurrences of lood circuit clotting nd the regulrity of the sessions ws not compromised y hypotensive episodes or other clinicl prolems. Hydrulic ptterns The men trend of the hydrulic pressure in the lood comprtment t the infusion (P inf ) nd the lood inlet port (P Bin ) during the sessions of stndrd MD-HDF with the MD-19 dilyser nd reverse MD-HDF with the MD-22 dilyser is shown in Figure 2A nd C, respectively, nd the corresponding trends of the TMP in Figure 2B nd D. TMP in the first post-dilution section of the lood comprtment progressively incresed during the stndrd MD-HDF sessions from men initil vlue of mmhg, stilizing t mmhg in the lst hour nd rising to very high men vlue of 722 ± 16 mmhg t the end of the sessions. Men vlues t the strt nd the end of the session nd the men of minute-y-minute vlues re reported in Tle 2. In stndrd MD-HDF, n increse in P inf eyond the estlished mximum vlue (65 mmhg) nd ssocited with very high P Bin of up to 1 mmhg ws recorded in 8 out of 15 ptients in the second hlf of their experimentl sessions (Figure 3), nd the control system of the device emitted repeted lrms requesting the infusion rte to e reduced mnully. As consequence, the men infusion rte in those eight ptients decresed from 155 ± 11 to 114 ± 12 ml/min in steps of 1 ml/min. As men of the 15 ptients, the infusion rte hd to e progressively reduced from 166 ± 14 to 144 ± 34 ml/min to void technicl nd clinicl prolems. In contrst, ll tretments with the MD-22 dilyser used in reverse configurtion were crried out without ny intervention to reduce the initil infusion rte (men 169 ± 2 ml/min) since P inf remined under the prescried limit in ll ptients. The men totl volume exchnge ws 37.5 l/session (1.1 l/h) in reverse MD-HDF nd 35.1 l/session (9.4 l/h) in stndrd MD-HDF (P =.47). Lower TMP ws necessry to mintin the plnned ultrfiltrtion rte, even if in the lst hlf hour of the session TMP vlues t the inlet lood port of the MD-22 dilyser rose eyond the upper limit of mmhg suggested y the memrne mnufcturer, up to men end-session vlue of 623 ± 13 mmhg (see Figure 2D nd Tle 2). The considerle difference in the pressure regimen originting in the two dilysers tested under similr operting conditions is sustntited y the reltive resistnce to lood entering the filter (Figure 4A nd Tle 2), which is significntly higher in stndrd thn in reverse MD-HDF, nd lso ppers from the inspection of Figure 5, where lood nd dilyste pressures, filtrtion pressure nd pressure drop in the two different section of the dilysers re depicted schemticlly. Comprison of the two pnels in Figure 5 clerly shows the gret difference in hydrulic pressure cting long the first post-dilution section of the two dilysers. The trend of the in vivo ultrfiltrtion coefficient during the experimentl tretments is shown in Figure 4B, nd

5 282 L. A. Pedrini et l. P, mmhg TMP, mmhg c A B P, mmhg TMP, mmhg c C D Fig. 2. Pnel A: men hydrulic pressure profile of ll experiments t the inlet lood port (P Bin, line ) nd t the infusion port (P inf, line ) of the OLpur TM MD-19 dilyser during stndrd MD-HDF. Pnel B: men filtrtion pressure (TMP) profile of ll experiments, s clculted from eqution (5), t the inlet lood port (line ), t the infusion port (line ) nd t the outlet lood port (line c) during stndrd MD-HDF. In pnels C nd D, the sme men pressure profiles recorded during reverse MD-HDF with the OLpur TM MD-22 dilyser re shown. Numericl vlues nd sttistics re reported in Tle 2. the men vlues t the strt nd the end of the sessions re reported in Tle 2. K I is n index of the in vivo permeility to wter of the memrne, which my e ffected y n enhncement of the protein polriztion phenomenon with thickening of the secondry protein lyer due to excessive pressure exerted on the memrne, s possily occurred in this study to greter extent during the sessions with the MD-19 dilyser. Efficiency of dilysers nd procedures The concentrtions of the exmined prmeters t the strt nd the end of the experimentl sessions re reported in Tle 3. Only ure end-session vlues exhiited significnt differences etween the two procedures. Instntneous β2-m clernce t the strt of the session (Tle 4) ws similr to the two compred tretments. However, the tendency to decline during the session ws less pronounced during reverse MD-HDF with the MD-22 dilyser (21% versus 32%), with the result tht end-session β2-m K I vlues were significntly higher thn those clculted during stndrd MD-HDF with the MD-19 dilyser. This resulted in overll β2-m removl tht ws significntly greter with the reverse MD-22 HDF tretments. In ddition, the men β2-m K DQ of the sessions ws higher in solute vlues during reverse MD-HDF nd the difference etween the two tretments ws very close to sttisticl significnce. Phosphte removl ws similr in terms of mss recovered in the dilyste nd men K DQ while, surprisingly, stndrd MD-HDF with the MD-19 dilyser showed greter ility to remove smll molecules, s demonstrted y the significntly higher men ure K DQ nd ekt/v vlues compred with those otined during reverse MD-22 HDF. Inversion of oth lood nd dilyste lines, tested in the sme ptients of the study in supplementry sessions of reverse MD-HDF, did not produce significnt effects on the efficiency of the technique in removing ure (K DQ 252 ± 29 versus 254 ± 33 ml/min, ekt/v 1.49 ±.17 versus 1.52 ±.21, in reverse versus doule reverse MD- HDF, respectively). Phosphte nd β2-m removl were not compred in reverse versus doule reverse configurtions. Discussion Mid-dilution HDF ws originlly proposed s technique tht ws le to wrrnt lrge ultrfiltrtion volumes nd consequently the mximl middle moleculr solute removl y convection. Indeed, reported β2-m (11.8 kd), cysttin

6 Mid-dilution HDF 2821 Tle 2. Hydrulic pressure nd indexes during the experimentl A procedures 12 Stndrd MD- Reverse MD- HDF (MD-19) HDF (MD-22) (n = 15) (n = 15) P-vlue P B inlet (mmhg) Strt session 665 ± ± 93.6 End session 896 ± ± Men of the session 835 ± ± 132 <.1 P inf. (mmhg) Strt session 424 ± ± 45 <.1 End session 559 ± ± 52 <.1 Men of the session 524 ± ± 53 <.1 P B outlet (mmhg) Strt session 153 ± ± 23 n.s End session 172 ± ± 27 n.s. Men of the session 164 ± ± 26 n.s. TMP inlet (mmhg) Strt session 58 ± ± 74 n.s End session 722 ± ± 13.5 Men of the session 683 ± ± TMP inf. (mmhg) Strt session 17 ± ± 25 <.1 End session 295 ± ± 38 <.1 Men of the session 27 ± ± 34 <.1 TMP outlet (mmhg) Strt session 4 ± 28 4 ± 9 <.1 End session 3 ± ± Men of the session 16 ± ± 12.9 Resistnce index (mmhg/ml/min) Strt session 1.78 ± ±.2.45 End session 2.37 ± ±.33.4 K UF (ml/h/mmhg/m 2 ) Strt session 32.7 ± ± 7.5 <.1 End session 19.9 ± ± 6. <.1 Arevitions nd definition of the prmeters re in the text (see the Sujects nd methods section). Dt re presented s mens ± SD. Student s t-test for pired dt. A proility vlue of <.5 ws considered significnt. P Bin, mmhg P Bin, mmhg B Fig. 3. Hydrulic pressure profile of individul experiments t the inlet lood port (P Bin ) of the OLpur TM MD-19 dilyser during stndrd MD- HDF (pnel A) nd of the OLpur TM MD-22 during reverse MD-HDF (pnel B). The dotted line is the men of ll experiments. C (13.4 kd) nd retinol-inding protein (21.2 kd) clernces were significntly higher thn those otined in post-dilution HDF [8]. However, fter its initil clinicl ppliction it ws shown tht during MD-HDF, considerly high hydrulic pressures my rise in the nnulr section of the lood comprtment of the MD-19 dilyser, where post-dilution tkes plce [1]. These criticl events nd the inherent risk, which hd not een ddressed in the originl vlidtion study of the technique [8], hve een confirmed y the results of the present study in lrger su-set of ptients nd hve lso een reported y other uthors [11], who recorded men TMP of up to 1 mmhg in the first post-dilution section of the MD-19 dilysers, even in sessions performed with sustntilly lower infusion rtes thn ours (6 versus 1 l/h). A hypotheticl explntion of these high pressures [1] ws the high resistnce to lood entering the post-dilution section of the dilyser, where the overll surfce re of the cpillries is reltively smll (1.1 m 2 ). As lso shown in the present study (Figures 2 nd 3), resistnce further incresed during the session s consequence of the progressive hemoconcentrtion long the fires tht incresed lood viscosity nd required proportionlly incresing pressure to chieve nd mintin the set lood flow. In these conditions, the plnned filtrtion could not e fully mintined even with the very high TMP vlues progressively set y the mchine s volumetric ultrfiltrtion control. The preliminry results otined in few ptients, with dilyser of lrger surfce re (the MD-22 filter, 2.2 m 2 ) used in stndrd configurtion [12], seemed to support the ove hypothesis: less resistnce to lood nd lower pressure were recorded in the lrger lood comprtment section of this dilyser where post-dilution occurred, even t high lood nd infusion rtes of nd 2 ml/min, respectively. However, definite improvement in hydrulics ws only descried when oth dilysers were used in reverse configurtion [11,12]. Since in this cse the post-dilution process occurs in the core region of the fire undle of the dilysers rther thn in the nnulr externl section, these lst oservtions seem to contrdict the former hypothesis, the overll surfce of the core cpillries eing smller thn tht of the nnulr region in oth dilysers. Our present study confirmed tht reverse MD-HDF with the MD-22 dilyser ensures sustntilly higher level of sfety thn stndrd MD-HDF with the MD-19 dilyser, requiring lower pressure regimen to otin high

7 2822 L. A. Pedrini et l. Res Index 2,6 2,4 2,2 2, 1,8 1,6 1,4 1,2 1, A K UF, ml/h/mmhg/m B Fig. 4. Men ehviour of ll experiments of the resistnce index R I (pnel A)ndthein vivo ultrfiltrtion coefficient of the dilyser memrne K UF (pnel B), s clculted from equtions (6) nd (7), respectively nd recorded on-line during stndrd MD-HDF (line ) nd reverse MD-HDF (line ). Numericl vlues nd sttistics re reported in Tle 2. P, mmhg P, mmhg A rteril port infusion-port venous port B rteril port infusion-port venous port Fig. 5. Schemtic representtion of the men filtrtion pressure (TMP) cting t different points long the length of the cpillries (from the rteril port to the venous port), expressed s men vlue of the stndrd MD-HDF sessions (pnel A) nd reverse MD-HDF (pnel B). Vlues of the men filtrtion pressures, clculted from eqution (5), re enclosed in the lck squres eside the thick verticl lck rrows tht represent the direction of the trnsmemrne pressure grdient. Thick lines nd rrows (in red, upper prt) represent lood flux nd its direction in the two lood comprtments, while thin lines nd rrows (green, lower prt) represent the dilyste flux. Men pressure vlues t the inlet, mid nd outlet lood nd dilyste ports of the filter re lso reported (see lso Tle 2). Vlues in smll chrcters long the lood lines re the pressure drop in the two lood comprtments of the dilyser Tle 3. Bseline nd end-session ptient prmeters Stndrd MD- Reverse MD- HDF (MD-19) HDF (MD-22) (n = 15) (n = 15) P-vlue Ure (mg/dl) Strt ± ± 3. n.s. End 25.7 ± ± (11 37) (21 48) Phosphte (mg/dl) Strt 4.5 ± ± 1.4 n.s. End 1.9 ± ±.7 n.s. β2-microgloulin (mg/l) Strt 19.2 ± ± 4.7 n.s. End 6.5 ± ± 2.4 n.s. Hemtocrit (%) Strt 34.7 ± ± 2.8 n.s. End 37.5 ± ± 3.7 n.s. Totl protein (g/dl) Strt 6.3 ± ±.5 n.s. End 6.6 ± ±.5 n.s. Dt re presented s mens ± SD. Student s t-test for pired dt. A proility vlue of <.5 ws considered significnt. ultrfiltrtion rtes. In fct, during reverse MD-HDF P B in nd P inf remined generlly within the sfe rnge, thus llowing the plnned ultrfiltrtion rte to e mintined throughout ll sessions, even if hzrdous men TMP vlues > mmhg were lso recorded in the reverse MD- HDF technique in the initil post-dilution section of the dilyser in the lst hlf hour of the sessions. However, the level of risk ws definitely lower in reverse MD-HDF thn in the cse of stndrd MD-HDF with the smller dilyser. Our comprison ws crried out etween dilysers with the sme memrne nd of similr surfce re devoted to post-dilution (nnulr region 1.1 m 2 in MD-19 nd core region 1. m 2 in MD-22) nd the pressure drop within the reltive post-dilution sections ws comprle under similr operting conditions (see Figure 5). Thus, it seems likely tht the high hydrulic pressures re needed to chieve the set lood flow through the reltively low cross-sectionl

8 Mid-dilution HDF 2823 Tle 4. Efficiency of the experimentl procedures mixed HDF [17], would e eneficil in improving sfety nd performnce in routine ppliction of the mid-dilution Stndrd MD- Reverse MD- HDF technique. It is importnt to e wre tht the TMP HDF (MD-19) HDF (MD-22) (n = 15) (n = 15) P-vlue vlue displyed on the monitor of the mchines commonly used in clinicl prctice, eing generlly clculted s the Ure Mss trnsfer (DQ) ± ± 11.5 n.s. difference etween P B out nd P D out, underestimtes the ctul filtrtion pressure t vrious points long the dilyser nd my e misleding when tken s reference (g/session) K DQ (ml/min) 272 ± ± 29.2 prmeter. ekt/v 1.63 ± ±.17.5 Phosphte The differences in efficiency etween the two MD-HDF Mss removl (mg) 839 ± ± 272 n.s. configurtions found in our study rose minly, in our opinion, from the different hydrulic conditions estlished in K DQ (ml/min) 128 ± ± 26 n.s. β2-microgloulin the post-dilution section of the two filters. It is well known K I strt session (ml/min) 116 ± ± 15 n.s. K I end session (ml/min) 79 ± ± tht extremely high filtrtion pressures, prticulrly in the Mss removl (mg) ± ± initil phse of the session, my cuse significnt deteriortion of memrne permeility to wter nd lrger solutes K DQ (ml/min) 66.6 ± ± [18,19], proly due to the progressive depositing nd Arevitions nd definition of the prmeters re in the text (see the thickening of the protein lyer on its surfce. The effects Sujects nd methods section). of these events were lso oserved in our study nd they Dt re presented s mens ± SD. Student s t-test for pired dt. A proility vlue of <.5 ws considered significnt. fct, the in vivo ultrfiltrtion coefficient of the dilyser, s ppered to e proportionl to the set filtrtion pressure. In n index of hydrulic permeility, decresed to greter extent during stndrd MD-HDF sessions with the MDre of the fire lumens, prticulrly in their sections where post-dilution occurs, ut the differences in pressure etween the two tretment configurtions cnnot e explined with differences in surfces. Insted, it my e resonly ssumed tht the higher pressure inside the post-dilution section of the MD-19 is consequence of the reduction of the overll surfce re of the cpillries from 1.1 to.8 m 2 t the point where lood flow reverses its direction (infusion port) nd its pth is constricted. This phenomenon, known s the Venturi effect or hydrodynmic prdox, is well-known consequence of the Bernoulli s principle of fluid dynmics. In contrst, during tretment with the MD- 22 dilyser (s well s with the MD-19) when used in reverse configurtion, the overll surfce of the cpillries increses t the pssge from the post- to the pre-dilution section nd lower pressure is required to counterct the resistnce creted y lrger cpillry surfce. It is unlikely tht mjor prt of the high resistnce to lood entering the MD-19 dilyser in the stndrd configurtion cn e ttriuted to the geometry of the spirl lood pth within the dul port heder cp of the dilyser, ut the role of this fctor remins indefinite. In ddition, the originl structure of MD-dilysers, coupled with the impossiility of otining lood smples from the mid-dilution port during tretment, prevented us from fully understnding the reciprocl reltionships etween their post- nd pre-dilution sections s regrds the dynmics of trnsmemrne fluid nd solute exchnges nd precisely estimting their rtes in the different sections. In the clinicl ppliction of MD-HDF, it would e dvisle to tilor the infusion rte ccording to the dilyser nd lood chrcteristics of the ptients (lood flow rte, hemtocrit, totl proteins, cogultion nd refilling properties), in order to prevent untowrd events relted to high pressures nd loss in efficiency due to deteriortion of the permeility chrcteristics of the memrne. Thus, n efficient pressure control system with on-line feedck modultion of the infusion rte, s relized in 19 dilyser thn during reverse MD-HDF with the lrger dilyser. Similrly, the trend of instntneous β2-m clernce, tken s surrogte index of chnges in memrne permeility to middle moleculr solutes, showed greter nd more significnt decline towrds the end of stndrd MD-HDF sessions compred to the reverse tretment (32% versus 17%). These events my explin why reverse MD- HDF yielded significntly greter β2-m removl thn stndrd MD-HDF in the sme ptients tested under mtched operting flux conditions. The reltive contriution to the overll solute trnsport of the post- nd pre-dilution sections of the dilyser could not e defined exctly, even if contriution of the pre-dilution mechnism to the incresed β2-m removl in reverse MD-HDF my e resonly presumed, due to the higher reltive surfce re of the dilyser (1.2 m 2 in MD-22 versus.8 m 2 in MD-19) nd the higher overll replcement volume. Phosphte removl ws in the high rnge with no sttisticl difference etween the two techniques. In contrst, removl of smll solule molecules (ure) in our study ws higher in stndrd MD-HDF thn in the reverse technique, s lredy reported, ut not explined, y other uthors [11]. We cn hypothesize tht this could e result of the prtil comprtmentliztion of the dilyste flux, which might permete the externl nnulr cpillries etter thn the core undle s consequence of the dilyser structure. In the nnulr region, which hs similr surfce re in oth dilysers (1.1 nd 1.2 m 2 in MD-19 nd in MD-22 respectively), the grdient for ure diffusion ws much higher during stndrd thn reverse MD-HDF, where ure extrction occurred from highly diluted lood. On the other hnd, the higher filtrtion pressure cting in the MD-19 dilyser could lso promote greter removl of smll solute like ure which, unlike β2-m, ws not retined y the memrne even when its permeility hd deteriorted. Smll solutes re minly removed y diffusion, ut evidence exists tht high-volume exchnge HDF my provide non-insignificnt contriution to ure removl y

9 2824 L. A. Pedrini et l. convection [17]. As shown y compring reverse versus doule reverse MD-HDF, the direction of the dilyste flux did not hve ny significnt effects on solute trnsport. Thus, its preferentil comprtmentliztion in the nnulr region of the dilyser could explin t lest prtilly why ure removl ws less effective in reverse compred to stndrd MD-HDF. In conclusion, our study demonstrted the ility of MD-HDF to remove significnt mounts of medium-sized uremic compounds nd phosphte. Ure removl ws sufficient to ccomplish current dequcy criteri for smll solutes. Sfe opertionl conditions in terms of hydrulic pressure were more relily mintined y crrying out tretments with the dilyser used in reverse configurtion, s consequence of stted principle of hydrodynmics. For this purpose, the lrger MD-22 dilyser ensures etter tolernce together with higher middle molecules clernce. An efficient pressure control system with on-line feedck modultion of the infusion rte ccording to the ptient nd the dilyser chrcteristics nd the opertionl conditions of the tretments would e eneficil to improve sfety nd performnce in the routine clinicl ppliction of the mid-dilution HDF technique. Acknowledgements. Prt of the results of this study were presented t the XLV ERA-EDTA Congress, Stockholm, Sweden, 28 nd t the 54th ASAIO Annul Conference, Sn Frncisco, USA, 28. Conflict of interest sttement. L.A.P. hs, t present, temporry consultncy greement with Fresenius Medicl Cre, Bd Homurg, Germny. The other uthors declre no conflict of interest. References 1. Bmmens B, Evenepoel P, Vereke K et l. Removl of the proteinound solute p-cresol y convective trnsport: rndomized crossover study. Am J Kidney Dis 24; 44: Beerenhout CH, Luik AJ, Jeuken-Mertens SG et l. Pre-dilution on-line hemofiltrtion versus low-flux hemodilysis: rndomized prospective study. Nephrol Dil Trnsplnt 25; 2: Loctelli F, Mrcelli D, Conte F et l. Comprison of mortlity in ESRD ptients on convective nd diffusive extrcorporel tretments. The Registro Lomrdo Dilisi e Trpinto. Kidney Int 1999; 55: Mduell F, Nvrro V, Cruz MC et l. Osteoclcin nd myogloin removl in on-line hemodifiltrtion versus low- nd high-flux hemodilysis. Am J Kidney Dis 22; 4: Vslki L, Mjor L, Bert K et l. On-line hemodifiltrtion versus hemodilysis: stle hemtocrit with less erythropoietin nd improvement of other relevnt lood prmeters. Blood Purif 26; 24: Wrd RA, Schmidt B, Hullin J et l. A comprison of on-line hemodifiltrtion nd high-flux hemodilysis: prospective clinicl study. J Am Soc Nephrol 2; 11: Cnud B, Brgg-Greshm JL, Mrshll MR et l. Mortlity risk for ptients receiving hemodifiltrtion versus hemodilysis: Europen results from the DOPPS. Kidney Int 26; 69: Krieter DH, Flkenhin S, Chli L et l. Clinicl cross-over comprison of mid-dilution hemodifiltrtion using novel dilyzer concept nd post-dilution hemodifiltrtion. Kidney Int 25; 67: Krieter DH, Collins G, Summerton J et l. Mid-dilution on-line hemodifiltrtion in stndrd dilyzer configurtion. Nephrol Dil Trnsplnt 25; 2: Felicini A, Riv MA, Zeri S et l. New strtegies in hemodilfiltrtion (HDF): prospective comprtive nlysis etween on-line mixed HDF nd mid-dilution HDF. Nephrol Dil Trnsplnt 27; 22: Sntoro A, Ferrmosc E, Mncini E et l. Reverse mid-dilution: new wy to remove smll nd middle molecules s well s phosphte with high intrfilter convective clernce. Nephrol Dil Trnsplnt 27; 22: Krieter DH, Cnud B. New strtegies in hemodilfiltrtion (HDF) prospective comprtive nlysis etween online mixed HDF nd mid-dilution HDF. Nephrol Dil Trnsplnt 28;23: The EBPG Expert Group on Hemodilysis. Europen Best Prctice Guidelines for Hemodilysis: Prt 1. Nephrol Dil Trnsplnt 22; 17 (Suppl 7): Depner TA, Keshvih PR, Een JP et l. Multicenter clinicl vlidtion of n on-line monitor of dilysis dequcy. J Am Soc Nephrol 1996; 7: Dugirds JT. Simplified equtions for monitoring Kt/V, PCRn, ekt/v, nd epcrn. Adv Ren Replce Ther 1995; 2: Srgent JA, Gotch FA. Principles nd iophysics of dilysis. In: Jcos C, Kjellstrnd CM, Koch KM, Winchester JF (eds). Replcement of Renl Function y Dilysis. Dordrecht: Kluwer, 1996, Pedrini LA, De Cristofro V. On-line mixed hemodifiltrtion with feedck for ultrfiltrtion control: effect on middle-molecule removl. Kidney Int 23; 64: Dvid S, Cmi V. Hemofiltrtion: predilution versus postdilution. Contri Nephrol 1992; 96: Pedrini LA, Cozzi G, Frnn P et l. Trnsmemrne pressure modultion in high-volume mixed hemodifiltrtion to optimize efficiency nd minimize protein loss. Kidney Int 26; 69: Received for puliction: ; Accepted in revised form: