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Background: Blood flow (QB), dialysate flow (QD), and dialyser characteristics are the three major factors driving dialysis efficacy. Haemodiafiltration has added an increased convective volume to increase efficacy. We aimed to assess the influence of the infusion site of the replacement fluid in an in vitro system emulating haemodiafiltration., Methods: An in vitro system allowing us to control the dialysate temperature, concentration gradient, the flow of both dialyser sides over a range wider than that compatible with clinic, was set to evaluate the influence of the different parameters on dialysis efficacy. The total ion clearance was used as an accepted method for small molecule clearance assessment. Cellulose triacetate (CT190C, Baxter; FB170U, Nipro) and polysulfone (HF80, Fresenius) dialysers were included in the study. Dialysis as well as on-line diafiltration both with pre- and postdilutional infusion were assessed. The experimental conditions presented in this study included QD 620 and 970 ml/min. The convective flows ranged from 50 to 200 ml/min., Results: For a QD = 620 ml/min and a QB = 350 ml/min the total ion clearance ranged from 269 to 274 for HF80, from 291 to 294 for FB170 and from 294 to 302 for CT190. The variability of the measurements was very low (SD < 1%). Total ion clearance increased by 17-21% when QB was raised from 300 to 400 ml/min. Increasing QD from 420 to 970 ml/min (for QB = 350 ml/min), resulted in an increase in total ion clearance which was more marked at lower QD (from 420 to 620 ml/min) and plateaued thereafter (from 620 to 970 ml/min). Postdilutional on-line diafiltration with 100 ml/min of infusate resulted in an additional increase in total ion clearance of 5.4-8.6%. This increase was proportional to the infused volume. On the contrary, predilutional on-line diafiltration resulted in a decrease in total ion clearance which was also proportional to the infused volume (between -5.1 and -6.9% at 100 ml/min infusion volume and -9.7 to -12.9% at 200 ml/min)., Conclusions: The present in vitro system provided accurate and reproducible results on dialyser clearances. Our experiments confirmed previous studies on the influence of QB and QD on dialyser efficacy. Further, they show that the proportional increase in postdilutional on-line diafiltration is lesser than that previously reported. More importantly, they also show that pre-dilution infusion in high efficiency systems results in a drop in dialyser clearance compared to dialysis alone, again proportional to the infusion rate. Thus, increasing the convective flow may increase dialysis efficacy even more than increasing QD alone. However, the choice of infusion site is crucial to obtaining this benefit in small molecule clearances.

The estimation of Kt/V by utilization of the pre- and postdialysis urea concentrations (per cent reduction in urea and In(Upre/Upost)) provides a simple, quick technique that can be applied at the bedside. However, the accuracy of such techniques has been questioned. One possible reason for this inaccuracy may be the frequently observed postdialysis rebound in serum urea. We assessed the urea rebound at 30 min postdialysis in 34 haemodiafiltered patients and compared the calculation of Kt/V using this urea concentration with that using the immediate postdialysis concentration. These results were then compared to the Kt/V calculated by urea kinetic modelling (UKM), also utilizing the delayed serum urea concentration. The degree of urea rebound observed was large, 21.4%, being a reflection of the short-duration, rapid-flux dialysis. The formulae for calculation of Kt/V all significantly correlated with Kt/V by UKM but all gave results significantly different from Kt/V by UKM (P < 0.001 by paired t test). For assessment of Kt/V by these formulae or by UKM, the urea rebound is too large to ignore in the setting of short-duration, rapid-flux dialysis.

The reuse of dialyzers is widely practiced, especially in the United States. Despite this, the effects of reuse on the efficacy of removal of solutes and more recently proteins such as beta 2-microglobulin (beta 2M) are the subject of much debate. There is considerable evidence to suggest that reuse after cleansing and sterilizing with formalin, with or without bleach, maintains dialyzer performance. In this study, we have examined peroxyacetic acid use as the cleansing and sterilizing agent using Renatron machines. We analyzed reuse in 24 patients using polysulfone membranes in a hemodiafiltration (HDF) unit over a 2-year period. The mean maximum number of uses achieved was 20.1 +/- 0.5. Several factors considered clinically to influence the number of reuses achievable (hemoglobin, white blood cell, and platelet levels, erythrocyte sedimentation rate [ESR], and fibrinogen and total protein levels) were found not to influence the maximum number of uses obtainable. We then assessed prospectively the performance of 26 polysulfone dialyzers after peroxyacetic acid reprocessing up to 20 times, particularly with regard to their ability to remove beta 2M. We report that this combination of polysulfone membranes reprocessed with peroxyacetic acid used for HDF up to 20 times exhibits a maintained high level removal of compounds beyond a molecular weight (MW) of 12,000. Any secondary membrane formation that occurs appears not to influence the subsequent removal of beta 2M. Thus, we would recommend the use of peroxyacetic acid for reprocessing dialyzers in a safe and efficacious manner.

Although hemodiafiltration is purported to provide better cardiovascular stability for dialysis patients; other possible benefits of this therapy have not been well defined. We have compared treatment with hemodialysis (HD) and hemodiafiltration (HDF) in 20 stable patients over a period of 18 months. Dialysis parameters (dialysate composition and flow, duration, dialyzer) were the same in the two periods except for the added convection of HDF and a higher tolerated blood flow in HDF. Cardiovascular parameters were remarkably similar in the two treatment periods, indicating that stable patients do not benefit further from this therapy in terms of these factors. The clearance of urea was significantly improved with HDF, which was reflected in a higher Kt/V and lower TACurea. We observed a significant correlation between Kt/V and PRU in both HD and HDF modes. This correlation was linear and the regression line was similar in both modes. The clearance of beta 2-microglobulin was also significantly improved by HDF compared to HD. Thus the benefit of HDF in stable dialysis patients is the improved clearance of small molecules and beta 2-microglobulin without increasing dialysis time. Further clinical benefits due to the improved clearance may only become apparent with longer follow-up.

In an attempt to return to normal serum beta 2-microglobulin levels in a group of seven ESRD patients, a programme of daily HF with highly permeable AN69 membranes was undertaken. Pre-HF beta 2-M serum levels stabilized after 4 days at 20 mg/l, only 40% lower than the initial concentration. A total of 985 +/- 20 mg beta 2-M was removed over the week. The beta 2-M release rate averaged 97 micrograms/min with a broad range of values (63-128 micrograms/min). beta 2-M release peaked at 602 micrograms/min 1 h after the end of the HF session before returning to baseline by 12 h post-HF. We conclude that a return to normal blood beta 2-M concentrations in ESRD patients seems quite unrealistic despite a highly intensive extracorporeal therapy. Therefore other therapeutic alternatives have to be designed to prevent or cure beta 2-M amyloidosis.

The normal range for whole blood serotonin levels in chronic renal failure patients has not been defined. As serotonin may be implicated in platelet abnormalities, hypo- and hypertension and itch in dialysis patients, serotonin whole blood levels were measured in a group of patients with chronic renal failure and/or who were dialysis dependent. The levels were elevated in 12 patients with moderate (mean serum creatinine 335 +/- 54 mumol/l) chronic renal failure (270 +/- 46 micrograms/l) compared to 11 normals (163 +/- 17 micrograms/l, p less than 0.05; quoted normal range less than 300 micrograms/l) but did not correlate with serum creatinine levels. There was a marked elevation in serotonin levels in dialyzed patients, including those on hemodialysis (polysulfone, n = 6, 747 +/- 234 micrograms/l; cuprophane membranes, n = 6, 708 +/- 198 micrograms/l), hemodiafiltration (n = 12, 695 +/- 130 micrograms/l) and especially peritoneal dialysis (n = 6, 1,148 +/- 162 micrograms/l). All results were significant (p less than 0.01) compared to normals and compared to the nondialyzed group (p less than 0.05). The level of serotonin decreased during hemodialysis regardless of the membrane used. There was no positive correlation of serotonin levels with pruritus or hypertension, although there was a negative correlation with systolic blood pressure. The reference range for serotonin whole blood levels needs to be broadened when considering dialyzed patients.

Despite its potential advantages HDF has not gained large clinical acceptance among nephrologist due to its technical complexity and to the large quantity of pharmaceutical substitution fluid needed. HDF with on-line production of substitution fluid from dialysate simplifies the procedure and reduces the cost of treatment session. We treated regularly 13 high risk and/or non-compliant patients (9 males, 4 females) with HDF for 46 +/- 17 months. HDF program consisted of 3 sessions weekly lasting 210 +/- 10 mn with blood flow rate 350 +/- 20 ml/mn and fluid volume exchange of 20 liters/session. High flux dialyzers (HF80, Filtral 16) were reused 6 to 13 times automatically on a Renatron machine with peroxyacetic acid solution as sole cleaning and disinfecting agent. Microbiologic quality of infusate was assessed by membrane filtration culturing method and LAL endotoxin determination. 3937 HDF sessions were performed. 57.140 I of substitution fluid were infused IV to patients. Eight pyrogenic reactions were observed: 2 due to septicemia related to catheter infection and 6 from unknown origin. Adequacy of program was achieved in all patients. Blood pressure control was satisfactorily obtained without antihypertensive medication in 12/13 patients. Effective weekly integrated urea clearances was 150 +/- 15 l/wk, KT/V index was 1.50 +/- 0.10, urea TAC 20 +/- 2 mM/l and protein catabolic rate 1.40 +/- 0.10 g/kg/24 h. We conclude that HDF with on-line production of bicarbonate substitution fluid is a safe and highly efficient method cost-competitive with bicarbonate HD, which offers an interesting alternative for renal replacement therapy.

Safety and efficacy of a recently developed hemofiltration (HF) system with in-line production of substitution fluid (GHS-10; Gambro, Lund, Sweden) based on a sterilizing filtration of acetate buffered dialysate has been evaluated in 4 patients over a 6-month period. Two patients were prematurely excluded from the study: 1 because of acetate intolerance and the other because of kidney transplantation. Two patients completed the study (240 HF sessions). Treatment adequacy was maintained in the 2 medium term treated patients according to the usual clinical and biochemical criteria and a mean exchange volume of 100-105 liters/week (30-35 liters/session three times weekly). Urea kinetic modeling analysis performed over all HF cycles gave the following results: dialysis index (urea clearance.time-on HF/urea volume space) (KT/V) approximately 1-1.1, urea time averaged concentration (UREA TAC) approximately 15-20 mmol/l, and protein catabolic rate (PCR) approximately 1.1-1.2 g/kg/day. Rare clinical adverse symptoms observed during the course of sessions were attributed to acetate intolerance. Microbiological safety was confirmed in vivo by the absence of pyrogenic reactions after 240 HF sessions (approximately 7 m3 substitution fluid infused intravenously) and in vitro by the constant absence of bacteria and/or endotoxin content limulus amaebocyte lysate (LAL) sensibility threshold 10 pg/l within the infusate produced during the sham HF sessions. The fluid mass balance obtained with the GHS-10 monitor was excellent. The electrolyte composition as judged by Na variation remained in a range of 2-3%. GHS-10 used in this study for postdilutional HF confirms that a large quantity of intravenous quality fluid may be safely produced by ultrafiltration from dialysate. It also introduced a new dimension in biocompatibility of dialysis by demonstrating that sterile dialysate may be routinely produced and used for routine dialysis.

Prostacyclin (PGI2), the most potent and short-lived antiplatelet agent known today, has been used successfully as an antithrombotic in hemodialysis (HD). However, its vasodilatory effect has been the source of blood pressure instability in acetate HD and has restricted its use to bicarbonate HD. The authors took advantage of the better cardiovascular stability obtained with hemofiltration (HF) to compare the effects of PGI2 versus heparin either with acetate or bicarbonate HF in 4 patients. Efficacy of PGI2 in preventing thrombosis of the extracorporeal circuit was demonstrated in all cases with a dose of 4 ng/kg/min. HF performances remained unaffected whatever antithrombotic agent was used. Platelet activation as shown by BTG and PF4 release was inhibited by the PGI2 infusion. Platelet proteins release was greater with acetate HF, suggesting that acetate may have a specific role in platelet activation. Although the use of PGI2 was straightforward, it is worth noting that PGI2 partially suppressed the cardiostability usually associated with acetate HF. We conclude that the efficacy of PGI2 was well maintained in spite of conditions of high platelet shear stress conditions, but also that PGI2 potentiated the vasodilatory effect of acetate and suppressed partially the cardiovascular benefits of HF.