Optimizing renal replacement therapy—a case for online filtration therapies?

Charles H. Beerenhout1, Jeroen P. Kooman1,, Antinus J. Luik2, Suzanne G. J. Jeuken-Mertens2, Frank M. van der Sande1 and Karel M. L. Leunissen1

1 Department of Internal Medicine/Nephrology, University Hospital Maastricht, Maastricht and 2 Department of Internal Medicine, St. Maartens Gasthuis, Venlo, The Netherlands

Keywords: convective therapy; online filtration; solute clearance; sterility

Introduction

Ideally, renal replacement therapies (RRT) would mimic the function of the normal kidney. However, this goal is not approached both by the discontinuous nature of the treatment and by the fact that the clearance characteristics of the artificial kidney do not even approximate those of the normal human kidney. Haemodialysis and, to a somewhat lesser degree, peritoneal dialysis, which mainly operate by diffusion, preferably remove small molecules but do not remove a large amount of larger molecules that are normally cleared by the kidney. In contrast, haemofiltration (HF) and haemodiafiltration (HDF) are treatment modalities that, due to their convective nature, more closely approach the function of the normal kidney [1]. However, after a burst of initial attention, enthusiasm for these techniques declined during the 1980s, probably because of economic motives due to the high costs of the pharmaceutically prepared substitution fluid and, in the case of HF, because of the limited removal of small molecules.

By online preparation of substitution fluid from reverse osmosis water and dialysate concentrates, cleansed by multiple filtration steps, it has become possible to produce almost unlimited amounts of this solution in an economically feasible way. By the use of high volumes of substitution fluids, it also has become possible to circumvent the problem of the limited small molecule clearance. Nowadays, online filtration techniques have been introduced in various European countries. Nevertheless, hard outcome data comparing these techniques with standard dialysis treatment modalities are scarce.

The goal of this review is to present information on the technical and clinical aspects of online H(D)F treatment modalities and to address the question of whether these techniques deserve further consideration as routine dialysis modalities in patients with end-stage renal disease (ESRD). For discussion of modified HDF modalities, such as acetate-free biofiltration, paired filtration dialysis or HDF with online reinfusion of regenerated ultrafiltrate, the reader is referred to recent papers [2,3].

Potential role of middle molecules in dialysis-related complications

It is remarkable that, except for ß2-microglobulin (12 000 Da) and parathyroid hormone (9000 Da), the pathogenetic role of the so-called middle (300–12 000 Da) and larger molecules in complications of ESRD has remained somewhat obscure despite elaborate pioneering work in the 1970s, followed by that of later authors [4,5]. Recent developments, however, have shed new light on the potential pathogenetic role of middle molecular substances in ESRD patients, especially with regard to cardiovascular, nutritional and inflammatory complications in ESRD.

Substances of potential interest in the pathogenesis of cardiovascular complications are advanced glycation endproducts (AGE), which have been shown to accumulate in renal failure. Many AGE compounds have a molecular weight of 10 kDa or less [6]. The biological actions of these substances are various and include stimulation of cytokine production [7], inactivation of nitric oxide and detrimental effects on vascular endothelial function [8]. Several AGE compounds are markedly reduced by high-flux haemodialysis (up to 60%), but concentrations return to pre-treatment values within 3 h after dialysis [9]. Middle molecules may also have an effect on the lipid profile of dialysis patients, as a 5–20 kDa subfraction of uraemic serum was shown to inhibit apolipoprotein A-1 secretion [10].

Accumulation of MW molecules might also have relevance for the nutritional state of patients on RRT. In rats, ingestion of as yet unidentified uraemic toxins in the range of 2–5 kDa led to suppression of food intake [11]. It has also been suggested that leptin (16 kDa), for which serum levels are increased in chronic renal failure [12], has an appetite-suppressing effect in uraemic patients [13].

With regard to inflammatory complications, one of the substances of potential interest is complement factor D, which is a protein (24 kDa) involved in regulating the alternative pathway of complement. Complement factor D accumulates in renal failure, which may lead to enhanced complement activity in renal failure. Conversely, removal of complement factor D resulted in a diminished generation of active complement products [14]. For information on other potentially important middle molecular substances, such as granulocyte inhibitory proteins, which may play a role in the impaired neutrophilic response in dialysis patients, the reader is referred to excellent recent reviews [15,16].

Aspects of solute clearance

As the velocity of a substance is inversely related to its weight, smaller molecules are cleared more rapidly than larger molecules by techniques operating by diffusion. It will be clear that the use of a more permeable membrane will only circumvent this problem to a limited degree. In principle, filtration techniques based solely on convection leave only the filtrated volume, the degree of dilution (in pre-dilution mode) and permeability of the membrane as the limiting steps for solute clearance. It is now that the point where the fluid is infused comes into play. When the substitution fluid is infused after the artificial membrane (post-dilution), the filtration rate should not be increased above one-third of the blood flow, as otherwise the degree of haemoconcentration in the membrane will become too high. In the case of HF, this will lead to a limitation in solute clearance. In order to increase small and middle molecular clearance to its maximum during HF, the substitution fluid has to be infused in pre-dilution mode, which has the advantage that the blood may be diluted before entering the filter and, thus, higher filtration rates (up to 400 ml/min) are possible. In general, in pre-dilution mode, blood is diluted by a factor of one. Therefore, by definition, the total amount of fluid that has to be filtered (i.e. the plasma water and the infusate) in order to achieve a Kt/V of 1 in pre-dilution mode is twice the urea distribution volume [1,17].

Due to the combined effect of convection and diffusion, small molecular clearance is far greater during HDF compared with HF. However, when using HDF, the use of the pre-dilution mode, which would permit the highest middle molecular clearance due to the allowance of higher filtration rates, has the theoretical disadvantage that blood becomes less concentrated, reducing the diffusion gradient and thus small molecular clearance. In comparative studies, the difference in urea clearance between pre- and post-dilution differed between 2 and 17 ml/min [18,19]. In general, the difference in small molecular clearance between pre- and post-dilution appears to be larger when higher filtration rates are used [18].

In post-dilution mode, solute clearance is directly related to the filtrated volume, which is in turn dependent upon the achieved blood flow [18,20]. However, as mentioned previously, application of high filtration rates in post-dilution mode may lead to high transmembranous pressure (TMP) gradients in the artificial kidney due to haemoconcentration. Depending on the blood flow, this would generally limit the filtration rate (for undiluted plasma water) to 100–150 ml/min. Therefore, it has been proposed to combine pre- and post-dilution during online HDF in order to avoid excessive haemoconcentration [19]. This was shown to result in comparable clearance characteristics compared with post-dilution HDF at lower TMP. Nevertheless, a potential disadvantage of this method is its relative complexity and, until now, its clinical application appears to be limited.

In clinical studies that compared online filtration techniques with conventional dialysis therapies, urea clearance during pre-dilution HF was found to be comparable to low-flux dialysis [21], whereas post-dilution HDF was found to be comparable to high-flux dialysis, provided that the same surface area of the membrane was used [22]. Interestingly, however, an increase in phosphate clearance of more than 30% was observed when patients were changed from high-flux dialysis to online HDF using the same membrane surface area [22].

Sodium removal appears to be less during both pre-dilution HF and post-dilution HDF compared with low-flux haemodialysis with the same sodium concentrations in substitution fluid and dialysate, and seems comparable to haemodialysis with a sodium concentration of 2.7–4.0 Eq/l above the prescribed concentration for HDF [19,21]. This might be explained by an interfering effect of the Donnan factor on sodium removal. Although it would be expected that sodium transport would be even more affected during post-dilution modalities due to increased haemoconcentration, leading to an augmentation of the Donnan factor [23], a recent study did not show a difference in sodium removal between pre- and post-dilution HF [21].

Calcium kinetics during HDF are greatly dependent upon calcium concentration of the infusate and dialysate, but also upon the rate and the mode of infusion. Higher filtration rates (above 70 ml/min) [24] counteract the diffusive gain of calcium from dialysate to blood. Moreover, the use of the pre-dilution mode may further augment a negative calcium balance because of dilution of plasma proteins binding calcium [19]. Nevertheless, one study which assessed calcium mass transfer during online HDF showed a negative calcium balance only during prescription of a 1.25 mmol/l concentration in dialysate and infusate [25], whereas another study showed a negative calcium balance with the use of 1.50 mmol/l concentrates [26].

Regarding ß2 microglobulin, removal rates appear to be ~25–30% [2729] higher during online filtration techniques compared with high-flux haemodialysis, depending upon the filtrated volume [28]. It was shown that ß2 microglobulin clearance during HDF exceeded the clearance during high-flux haemodialysis at rates above 60 ml/min [28]. Nevertheless, in comparative studies, the change in pre-dialytic ß2 microglobulin levels during online HDF and high-flux dialysis varied between virtually no difference [27] and 30% lower levels during online HDF [29].

Comparable studies between online filtration techniques regarding other potentially relevant substances, such as AGEs, have yet to be performed. Nevertheless, leptin was found to be significantly removed both by HDF and by high-flux dialysis [30]. Conversely, complement factor D was lowered by a significantly larger degree during online HDF than during high-flux dialysis [27].

With regard to the effect of different membranes on middle molecular clearance, no clinically important differences appear to be present between the most commonly used dialysis membranes for online filtration therapies (i.e. polysulfone or polyamide), despite potential differences in absorption [3133].

A question which remains is whether potentially useful substances are lost during convective modalities. Although research into this matter is at present far from complete, available data do not show evidence of such a phenomenon, other than described for haemodialysis [3437], nor were signs of vitamin or electrolyte deficits reported in long-term clinical studies. Also, no albumin loss was observed with artificial membranes commonly used for convective therapies [31].

Safety aspects

It is evident that substitution fluid for online treatments, which is infused directly into the patient without separation by a semipermeable membrane, has to meet the strictest microbiological criteria for sterility [1,17,38,39]. The basic mechanism by which sterility is achieved is the use of ultrafilters, where contaminants are both cleared by means of restricted passage through the membrane, as well by absorption into the membrane. Also, the passage of endotoxin fragments, which are below the cut-off point of the membrane, is restricted. Membranes used for water treatment for online treatments are able to reduce bacteria and endotoxin fragments by at least 107 and 103, respectively [1,17,39].

Despite similarities with regard to the principle of ‘cold sterilization’, the two main systems that are commercially available differ in the handling of the incoming water and the substitution fluid. The Fresenius® ONLINEplusTM system uses two ultrafilters; the first is placed after the proportioning system and the second, which serves as a safeguard in case of loss of integrity of the first filter, is positioned before the substitution port. The two ultrafilters are replaced after a definite time period and are tested for integrity before each treatment [38,39]. The Gambro® AK-200 ULTRA system uses three ultrafilters (the first serving to filter the incoming water into the machine, the second being placed after the proportioning system and the third serving as a final ultrafilter to ensure sterility just before infusion into the patient), of which the final one is replaced after every treatment [40].

Both manufacturers state that, when pre-treated water is used according to AAMI standards, sterility of the final water is ensured. This is also stated in the CE-marking of the devices used for online HF, which are regarded as medical devices according to European guidelines [41]. However, these guidelines are not followed by all European countries, as, e.g. in the Netherlands, substitution fluids are considered as pharmaceutical compounds and therefore have to comply with the European Pharmacopea.

Nevertheless, also from the side of quality control, it appears prudent to consider the quality of the feeding, i.e. the reverse osmosis water. According to a recent survey, in more than 18% of centres in Germany dialysis water had a bacterial content >200 CFU/ml [42]. Moreover, although standard water treatment systems, which are not disinfected regularly, may be well able to produce water according to current pharmacopeas, it has been shown that in these systems extensive biofilm formation can occur, which may lead to a continuous state of contamination in the water treatment system. This is in contrast to a water treatment system that is disinfected on a regular basis, in which a virtual absence of biofilm formation in the most vulnerable part of the system (i.e. the connecting tube between the ring piping and the dialysis module) was reported after a 3 month period [43].

Due to the impressive absorbing capacities of the ultrafilters, even contamination of the feeding water beyond the standards indicated by the manufacturer does not have to result in major clinical problems if ultrafilters are replaced according to the advice of the manufacturers; however, according to the CE-marking of the devices, there also remains a matter of responsibility with the user when they are not absolutely sure that the feeding-water quality strictly adheres to the standards indicated by the manufacturers at all points in time. In the studies in which online substitution fluids were used, none showed negative results in terms of safety. Measurements of cytokine induction did not show any difference between online HDF and conventional dialysis techniques [44,45].

Regarding culturing of the infusate, it is important to consider the fact that a suitable amount (i.e. 1000 ml) is needed in order to show the sterility of the fluid. Cultures should be performed in nutrition-poor media (TGEA or R2A) at two different temperatures (22 and 37°C) during sufficiently long incubation times (7 days) [46,47].

For the surveillance for endotoxins in the infusate, it appears desirable to use a quantitative method (e.g. the kinetic chromogenic assay) that is able to detect low levels of contamination (<0.03 IU/l) [39]. Nevertheless, for the reasons indicated above, it is the strong personal belief of the authors that water treatment, when using online techniques, should be based on progressive risk reduction steps based on the concept of quality assurance. Although regular cultures and endotoxin testing of fluids is certainly of importance in terms of quality control, it should be stated that these only yield retrospective safety. Risk reduction steps should also take into account both the design and maintenance (regular disinfection) of the water treatment system. In order to achieve this goal, various designs of water treatment systems are possible [39].

Costs

Online filtration therapies are certainly more expensive than low-flux dialysis therapies. However, it should be taken into account that the use of high-flux dialysis with ultrapure dialysate is also much more expensive than conventional low-flux dialysis with water of standard bacteriological quality. Extra costs for online therapies above conventional low-flux dialysis include the use of larger membranes, additional ultrafilters and infusion lines (with or without disposable ultrafilters depending on the method used), costs for cultures and endotoxin determinations, and additional disinfection procedures of the dialysis module. Roughly calculated, not taking into account the additional costs for monitoring of fluids and with some hedging, the extra costs for one online filtration treatment would be approximately E6–21 compared with high-flux ‘ultrapure’ dialysis and E17–32 compared with conventional low-flux dialysis, this of course depending upon local conditions.

Influence of convective techniques on short-term complications

One of the most distressing acute complications during haemodialysis is haemodynamic instability. It has long been known that haemodynamic stability is in general better maintained during convective treatments [48]. This was also corroborated in recent studies applying online pre-dilution HF [35,36]. The difference in haemodynamic response between diffusive and convective treatments appears to be mainly based on differences in vascular reactivity, although some authors stated that a better plasma volume preservation by reduced sodium removal may also play a role [49]. In contrast to the inadequate response (i.e. insufficient constriction) of both resistance and capacitance vessels generally observed when fluid is removed, the vascular response during HF appears to be more physiological [48]. Although various mechanisms have been proposed as a cause for the inadequate vascular response during haemodialysis, it is highly likely that an increase in core temperature during standard haemodialysis treatment, which may lead to vasodilation of the cutaneous arteries and venules [50], may play an important role in this aspect. Interestingly, when matched for extracorporeal blood temperature, differences in vascular and/or blood pressure response between haemodialysis, HF and HDF disappeared [51,52]. Thus, although it has been suggested that an increased removal of middle-molecular vasodilating substances, such as calcitonine, may be implicated in the improved vascular response during haemodialysis [36,53,54], available data suggest that the impact of the removal of middle molecular weight substances, if present at all, at least appears to be limited [55].

Influence of convective techniques on long-term complications

Studies in order to investigate the influence of convective techniques on prevention of long-term complications have until now focused mainly on dialysis-related amyloidosis. Uncontrolled studies showed a delay in the need for surgery because of carpal tunnel syndrome and less complaints of arthralgias with the use of convective dialysis techniques [56,57]. The effect of convective therapy on interdialytic blood pressure is less clear, although in recent studies a decrease in antihypertensive medication was suggested [36,58]. However, no detailed studies towards the effect of convective therapies on cardiovascular structure are available as yet.

Concerning nutritional state in patients on RRT, no clear changes were found when comparing convective vs diffusive therapy, although body composition was not assessed in detail [36,37,58]. Uncontrolled studies suggested that online convective therapies could improve the response towards erythropoietin, e.g. by the removal of, as yet unidentified, erythropoiesis-suppressing toxins by convective therapy [58]. Nevertheless, in the two randomized studies available, comparing high-flux dialysis with online HDF, no difference in the erythropoietin response was observed [27,37]. Regarding quality of life, a tendency to improvement during pre-dilution HF was found, which did not reach statistical significance [36].

Finally, there are no prospective studies with sufficient power in which the effects of convective therapies were compared with those of other dialysis modalities. Earlier studies suggested a better survival of older and ‘poor-risk’ patients treated with post-dilutional HF compared with those treated with HD [59,60]. In a large survey comparing convective (HF and HDF) with diffusive therapy there was a trend, although not significant, towards a better survival in patients on convective RRT [56].

Thus, the effect of (online) convective therapies on long-term dialysis-related complications is not yet clear. This is also due to the fact that in several available studies, patients were not matched for the biocompatibility characteristics of the membrane. It can also not be excluded that the absence of contact with contaminated dialysate may have played a role in the suggested benefits of convective therapies. Moreover, changes in cardiovascular and nutritional state have until now not been assessed in detail during convective therapies. Therefore, there is a great need for controlled studies on effects of online convective therapies. Presently, a prospective randomized trial is being carried out in our centres, comparing pre-dilution online haemofiltration with (ultrapure) haemodialysis, in which body composition and cardiovascular structure are assessed in detail.

Conclusion

Online convective therapies offer the opportunity for as yet unrivalled small and/or middle molecular clearance in an economically feasible way, although it should be mentioned that due to the use of ultrafilters for purification of the substitution fluid, the need for larger artificial membranes, and the additional costs for microbiological surveillance, online convective therapies will be definitely more expensive than a standard dialysis treatment. Regarding short-term complications, there is ample evidence for the fact that haemodynamic stability is better maintained during haemofiltration techniques compared with standard haemodialysis, although it has never been shown that convective therapies are superior to haemodialysis when treatments were matched for thermal factors. Although mainly in uncontrolled studies a beneficial effect of convective therapies was suggested, there appears to be a shortage of well-controlled studies assessing the potential merits of online filtration techniques. Such studies are of great importance in order to convince politicians and health care insurance companies of the necessity for these more costly therapies. Both physiological studies, comparing in detail the effects of diffusive and convective therapies on cardiovascular and nutritional parameters, and larger studies, studying the effect of online filtration techniques on hard outcome data such as morbidity and mortality, are urgently needed to establish the role of these exciting treatment modalities in the next decade.

Notes

Correspondence and offprint requests to: Jeroen P. Kooman, Department of Internal Medicine/Nephrology, University Hospital Maastricht, Maastricht, The Netherlands. Email: Jkoo{at}groupwise.azm.nl Back

References

  1. Ledebo I. Does convective dialysis therapy applied daily approach renal blood purification? Kidney Int2001; 78 [Suppl]:S286–S291
  2. Tetta C, Ghezzi PM, de Nitti C, Fiorenza A, Cianciavecchia D, Gervasio R. New options for online hemodiafiltration. Contrib Nephrol2002; 137:212–220[ISI][Medline]
  3. Ding F, Ahrenholz P, Winkler RE et al. Online hemodiafiltration versus acetate-free biofiltration: a prospective crossover study. Artif Organs2002; 26:169–180[ISI][Medline]
  4. Furst P, Asaba M, Gordon A, Zimmerman L, Bergstrom J. Middle molecules in uraemia. Proc Eur Dial Transplant Assoc1975; 11:417–426[Medline]
  5. Vanholder R, De Smet R, Vogeleere P, Ringoir S. Middle molecules: toxicity and removal by hemodialysis and related strategies. Artif Organs1995; 19:1120–1125[ISI][Medline]
  6. Horl WH. Uremic toxins: new aspects. J Nephrol2000; 13 [Suppl 3]:S83–S88[ISI][Medline]
  7. Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science1988; 240:1546–1548[ISI][Medline]
  8. Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol2001; 12:1549–1557[Abstract/Free Full Text]
  9. Makita Z, Bucala R, Rayfield EJ et al. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet1994; 343:1519–1522[ISI][Medline]
  10. Kamanna VS, Kashyap ML, Pai R et al. Uremic serum subfraction inhibits apolipoprotein A-I production by a human hepatoma cell line. J Am Soc Nephrol1994; 5:193–200[Abstract]
  11. Anderstam B, Mamoun AH, Sodersten P et al. Middle-sized molecule fractions isolated from uremic ultrafiltrate and normal urine inhibit ingestive behavior in the rat. J Am Soc Nephrol1996; 7:2453–2460[Abstract]
  12. Heimburger O, Lonnqvist F, Danielsson A et al. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol1997; 8:1423–1430[Abstract]
  13. Stenvinkel P. Leptin—a new hormone of definite interest for the nephrologist. Nephrol Dial Transplant1998; 13:1099–1101[Free Full Text]
  14. Deppisch RM, Beck W, Goehl H, Ritz E. Complement components as uremic toxins and their potential role as mediators of microinflammation. Kidney Int2001; 78 [Suppl]:S271–S277
  15. Horl WH. Hemodialysis membranes: interleukins, biocompatibility, and middle molecules. J Am Soc Nephrol2002; 13 [Suppl 1]:S62–S71[Abstract/Free Full Text]
  16. Clark WR, Gao D. Low-molecular weight proteins in end-stage renal disease: potential toxicity and dialytic removal mechanisms. J Am Soc Nephrol2002; 13 [Suppl 1]:S41–S47[Abstract/Free Full Text]
  17. Ledebo I. On-line hemodiafiltration: technique and therapy. Adv Ren Replace Ther1999; 6:195–208[ISI][Medline]
  18. Lim PS, Lee HP, Kho B et al. Evaluation of pre- and postdilutional on-line hemodiafiltration adequacy by partial dialysate quantification and on-line urea monitor. Blood Purif1999; 17:199–205[ISI][Medline]
  19. Pedrini LA, de Cristofaro V, Pagliari B, Ruggiero P. Dialysate/infusate composition and infusion mode in on-line hemodialfiltration. Contrib Nephrol2002; 137:344–349[ISI][Medline]
  20. Ficheux A, Argiles A, Mion H, Mion CM. Influence of convection on small molecule clearances in online hemodiafiltration. Kidney Int2000; 57:1755–1763[ISI][Medline]
  21. Locatelli F, di Filippo S, Manzoni C. Removal of small and middle molecules by convective techniques. Nephrol Dial Transplant2000; 15 [Suppl 2]:37–44[Abstract/Free Full Text]
  22. Zehnder C, Gutzwiller JP, Renggli K. Hemodiafiltration—a new treatment option for hyperphosphatemia in hemodialysis patients. Clin Nephrol1999; 52:152–159[ISI][Medline]
  23. David S, Bostrom M, Cambi V. Predilution hemofiltration. Clinical experience and removal of small molecular weight solutes. Int J Artif Organs1995; 18:743–750[ISI][Medline]
  24. Vitale C, Marangella M, Ramello A. Dialysate/infusate calcium and magnesium. Contrib Nephrol2002; 137:350–356[ISI][Medline]
  25. Malberti F, Corradi B, Tetta C, Imbasciati E. Calcium balance and serum ionized calcium fluctuations in on-line haemodiafiltration in relation to ultrafiltration rate and dialysate calcium concentration. Nephrol Dial Transplant1994; 9:1759–1764[Abstract]
  26. Argiles A, Mion CM. Calcium balance and intact PTH variations during haemodiafiltration. Nephrol Dial Transplant1995; 10:2083–2089[Abstract]
  27. Ward RA, Schmidt B, Hullin J, Hillebrand G, Samtleben W. A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol2000; 11:2344–2350[Abstract/Free Full Text]
  28. Lornoy W, Becaus I, Billiouw JM, Sierens L, van Malderen P, D'Haenens P. Online haemodiafiltration. Remarkable removal of beta2-microglobulin. Long-term clinical observations. Nephrol Dial Transplant2000; 15 [Suppl 1]:49–54[Abstract/Free Full Text]
  29. Lin CL, Yang CW, Chiang CC, Chang CT, Huang CC. Long-term on-line hemodiafiltration reduces predialysis beta-2-microglobulin levels in chronic hemodialysis patients. Blood Purif2001; 19:301–307[ISI][Medline]
  30. Wiesholzer M, Harm F, Hauser AC, Pribasnig A, Balcke P. Inappropriately high plasma leptin levels in obese haemodialysis patients can be reduced by high flux haemodialysis and haemodiafiltration. Clin Sci (Lond)1998; 94:431–435[ISI][Medline]
  31. Nensel U, Rockel A, Hillenbrand T, Bartel J. Dialyzer permeability for low-molecular-weight proteins. Comparison between polysulfone, polyamide and cuprammonium-rayon dialyzers. Blood Purif1994; 12:128–134[ISI][Medline]
  32. Kramer BK, Pickert A, Hohmann C et al. In vivo clearance and elimination of nine marker substances during hemofiltration with different membranes. Int J Artif Organs1992; 15:408–412[ISI][Medline]
  33. Chanard J, Caudwell V, Valeire J et al. Kinetics of 131I-beta2 microglobulin in hemodialysis patients: assessment using total body counting. Artif Organs1998; 22:574–580[ISI][Medline]
  34. Morena M, Cristol JP, Bosc JY et al. Convective and diffusive losses of vitamin C during haemodiafiltration session: a contributive factor to oxidative stress in haemodialysis patients. Nephrol Dial Transplant2002; 17:422–427[Abstract/Free Full Text]
  35. Altieri P, Sorba G, Bolasco P et al. Pre-dilution haemofiltration—the Sardinian multicenter studies: present and future. Nephrol Dial Transpl2000; 15 [Suppl 2]:55–59[Free Full Text]
  36. Altieri P, Sorba G, Bolasco P et al. Pre-dilution haemofiltration—the second Sardinian multicenter study: comparisons between haemofiltration and haemodialysis during identical Kt/V and session times in a long term cross-over study. Nephrol Dial Transpl2001; 16:1207–1213[Abstract/Free Full Text]
  37. Wizeman V, Lotz C, Techert F. On-line haemodiafiltration versus low-flux haemodialysis. A prospective randomized study. Nephrol Dial Transplant2000; 15 [Suppl 1]:43–48[Abstract/Free Full Text]
  38. Passlick-Deetjen J, Pohlmeier R. On-line haemodiafiltration: gold standard or top therapy. Contrib Nephrol2002; 137:201–211[ISI][Medline]
  39. Canaud B, Bosc JY, Leray H et al. Microbiological purity of dialysate for on-line substitution fluid preparation. Nephrol Dial Transplant2000; 15 [Suppl 2]:21–30[Abstract/Free Full Text]
  40. Ledebo I. On-line preparation of solutions for dialysis: practical aspects versus safety and regulations. J Am Soc Nephrol2002; 13 [Suppl 1]:S78–S83[Abstract/Free Full Text]
  41. Pirovano D. Regulatory issues for on-line haemodiafiltration. Nephrol Dial Transplant1998; 13 [Suppl 5]:21–23[Free Full Text]
  42. Bambauer R, Schauer M, Jung WK, Daum V, Vienken J. Contamination of dialysis water and dialysate. A survey of 30 centers. ASAIO J1994; 40:1012–1016[Medline]
  43. Penders C, Kooman JP, Stobberingh EE, van der Sande FM, Frederik PM, Leunissen KM. Does ultrapure dialysate prevent the development of biofilm in dialysis therapy? Nephrol Dial Transplant2001; 16:1522–1524[Free Full Text]
  44. Canaud B, Wizemann V, Pizzarelli F et al. Cellular interleukin-1 receptor antagonist production in patients receiving on-line haemodiafiltration therapy. Nephrol Dial Transplant2001; 16:2181–2187[Abstract/Free Full Text]
  45. Vaslaki L, Karatson A, Voros P et al. Can sterile and pyrogen-free on-line substitution fluid be routinely delivered? A multicentric study on the microbiological safety of on-line haemodiafiltration. Nephrol Dial Transplant2000; 15 [Suppl 1]:74–78[Abstract/Free Full Text]
  46. Lonnemann G. On-line fluid preparation. Contrib Nephrol2002; 137:332–337[ISI][Medline]
  47. Ledebo I, Nystrand R. Defining the microbiological quality of dialysis fluid. Artif Organs1999; 23:37–43[ISI][Medline]
  48. Baldamus CA, Ernst W, Frei U, Koch KM. Sympathetic and hemodynamic response to volume removal during different forms of renal replacement therapy. Nephron1982; 31:324–332[ISI][Medline]
  49. Santoro A, Mancini E, Zucchelli P. The impact of haemofiltration on the systemic cardiovascular response. Nephrol Dial Transplant2000; 15 [Suppl 2]:49–54[Abstract/Free Full Text]
  50. van der Sande FM, Kooman JP, Leunissen KM. Intradialytic hypotension—new concepts on an old problem. Nephrol Dial Transplant2000; 15:1746–1748[Free Full Text]
  51. van Kuijk WH, Hillion D, Savoiu C et al. Critical role of the extracorporeal blood temperature in the hemodynamic response during hemofiltration. J Am Soc Nephrol1997; 8:949–955[Abstract]
  52. van der Sande FM, Kooman JP, Konings CJ, Leunissen KM. Thermal effects and blood pressure response during postdilution hemodiafiltration and hemodialysis: the effect of amount of replacement fluid and dialysate temperature. J Am Soc Nephrol2001; 12:1916–1920[Abstract/Free Full Text]
  53. Henderson LW. Hemodynamic instability during different forms of dialysis therapy: do we really know why? Blood Purif1996; 14:395–404[ISI][Medline]
  54. Ledebo I. On-line hemofiltration. Old concept—new approach. Contrib Nephrol2002; 137:221–226[ISI][Medline]
  55. Kooman JP, van der Sande FM, Leunissen KML. Predilution haemofiltration. Nephrol Dial Transplant2002; 17:171–172[Free Full Text]
  56. Locatelli F, Marcelli D, Conte F et al. Comparison of mortality in ESRD patients on convective and diffusive extracorporeal treatments. Kidney Int1999; 55:286–293[ISI][Medline]
  57. Nakai S, Iseki K, Tabei K et al. Outcomes of hemodiafiltration based on Japanese dialysis patient registry. Am J Kidney Dis2001; 38 [Suppl 1]:S212–S216[ISI][Medline]
  58. Maduell F, del Pozo C, Garcia H et al. Change from conventional haemodiafiltration to on-line haemodiafiltration. Nephrol Dial Transplant1999; 14:1202–1207[Abstract]
  59. Schaefer K, Asmus G, Quellhorst E et al. Optimum dialysis treatment for patients over 60 years with primary renal disease. Survival data and clinical results from 242 patients treated either by haemodialysis or haemofiltration. Proc EDTA-ERA1984; 21:510–517
  60. Quellhorst E, Scheunemann E, Mietzsch G. Long-term hemofiltration in ‘poor risk’ patients. Trans Am Soc Artif Intern Organs1987; XXXIII:758–764